Substituted bezopyran derivatives for the treatment of inflammation

ABSTRACT

A class of benzopyrans, benzothiopyrans, dihydroquinolines, dihydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula I′ 
                 
 
     wherein X, A 1 , A 2 , A 3 , A 4 , R, R″, R 1  and R 2  are as described in the specification.

RELATED CASES

[0001] This is a continuation in part of application Ser. No.09/062,537, filed Apr. 17, 1998, which is a continuation in part ofapplication Ser. No. 60/044,485, filed Apr. 21, 1997.

FIELD OF THE INVENTION

[0002] This invention is in the field of anti-inflammatorypharmaceutical agents and specifically relates to compounds,compositions and methods for treating cyclooxygenase-2 mediateddisorders, such as inflammation and inflammation-related disorders.

BACKGROUND OF THE INVENTION

[0003] Prostaglandins play a major role in the inflammation process andthe inhibition of prostaglandin production, especially production ofPGG₂, PGH₂ and PGE₂ has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

[0004] Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

[0005] Recently, there has been significant research into some of theroles of cyclooxygenase-2. It has been found that COX-2 is upregulatedin benign and malignant tumors (K. Subbaramaiah et al., Proc. Soc. Exp.Biol. Med., 216, 201 (1997)) including lung cancer (T. Hida et al.,Anticancer Res., 18, 775-82 (1998)), Barrett's esophagus (K. Wilson,Cancer Res., 58, 2929-34 (1998)) and skin cancer (S. Buckman et al.,Carcinogenesis, 19, 723-29 (1998)). It is expressed in airway cells withimplication in asthma (P. Barnes et al., Lung Biol. Health Dis., 114,111-27 (1998)). Cox-2 also has a role in pre-term labor, angiogenesis(M. Tsujii et al. Cell, 93, 705-16 (1998)), vascular rejection (M.Bustos, J. Clin. Invest., 100, 1150-58 (1997)), HIV induced apoptosis(G. Bagetta et al., Biochem. Biophys. Res. Commun., 244, 819-24 (1998)),neurodegeneration (T. Sandhya et al., Brain Res., 788, 223-31 (1998)),inflammatory bowel disease, colitis, (I. Singer et al.,Gastroenterology, 115, 297-306 (1998)), cerebral ischemia (S. Nogawa etal., Proc. Natl. Acad. Sci., 95, 10966-71 (1998)), hypertension (A.Nasjletti, Hypertension, 31, 194-200 (1997)), among others.

[0006] Drugs that inhibit cyclooxygenase affect colon cancer (T.Kawamori et al., Cancer Res., 58, 409-12 (1998)), allergic neuritis (K.Miyamoto et al., Neuro Report, 9, 2331-4 (1998)), dementia, burninfections (M. Shoup, J. Trauma: Inj., Infec., Crit care, 45, 215-21(1998)), cytomegalovirus infectivity (E. Speir et al., Circ. Res., 83,210-16 (1998)), lumbago (H. Bosch, Curr. Med. Res. Opin., 14, 29-38(1997)), among others.

[0007] The references below that disclose antiinflammatory activity,show continuing efforts to find a safe and effective antiinflammatoryagent. The novel benzopyran, dihydroquinoline, benzothiopyran anddihydronapthalene derivatives disclosed herein are such safe and alsoeffective antiinflammatory agents furthering such efforts. Thesubstituted benzopyran, dihydroquinoline, benzothiopyran anddihydronapthalene derivatives disclosed herein preferably selectivelyinhibit cyclooxygenase-2 over cyclooxygenase-1.

[0008] U.S. Pat. No. 5,618,843, to Fisher et al., generically describesacid substituted bicyclic moieties as IIb/IIIA antagonists. WO 94/13659,published Jun. 23, 1994, describes fused benzo compounds for thetreatment of CNS disorders. Manrao et al. (J. Indian. Counc. Chem., 12,38-41 (1996)) describes carboxy coumarinimide derivatives and theirantifungal activity. U.S. Pat. No. 5,348,976, to Shibata et al.,describes amide substituted benzopyrans as antifungals.

[0009] WO96/40110, published Dec. 19, 1996, describes benzopyranderivatives as tyrosine kinase modulators. Loiodice et al. (Tetrahedron,6, 1001-11 (1995)) describe the preparation of6-chloro-2,3-dihydro-4H-1-benzopyran carboxylic acids.

[0010] Clemence et al. (J. Med. Chem., 31, 1453-62, (1988)) describe4-hydroxy-3-quinolinecarbooxylic acids as starting material in thepreparation of antiinflammatories. Lazer, et al. (J. Med. Chem., 40,980-89 (1997)) describe benzothiopyran carboxylates as starting materialin the preparation of antiinflammatories.

[0011] U.S. Pat. No. 5,281,720, to Young et al., describes naphthoicacids as lipoxygenase inhibitors. U.S. Pat. No. 5,348,976, to Shibata etal., describes amide substituted benzopyrans as antifungals. U.S. Pat.No. 5,004,744, to Weissmiller et al., describes2H-benzopyran-3-carboxylic acid as an intermediate for pesticides. U.S.Pat. No. 4,814,346, to Albert et al., describes 3-phenylbenzopyrans as5-lipoxygenase inhibitors. U.S. Pat. No. 4,761,425, to Girard andRokach, describes 4-oxo-benzopyrans as leukotriene antagonists. U.S.Pat. No. 4,609,744, to Young et al., describes4-oxo-benzopyran-carboxylic acids as leukotriene antagonists. U.S. Pat.No. 5,082,849, to Huang et al., describes 4-oxo-benzopyrans asleukotriene antagonists. WO95/07274, published Mar. 16, 1996, describes2H-benzopyran-3-carboxylic acid as intermediates. WO88/04654, publishedJun. 30, 1988, describes 2H-benzopyran-3-carboxylic acid asintermediates. EP412,939, published Feb. 13, 1991, describes substitutedchromenes as 5-lipoxygenase inhibitors. JP2-22272 describesbenzopyran-3-carboxylic acids. JP59-29681 describes8-methoxy-benzopyran-3-carboxylic acid as an intermediate. Bunting et al(Can. J. Chem., 62, 1301-07 (1984)) describes the synthesis of2-hydroxy-1,2-dihydro quinolines. Ukhin et al (Izv. Akad. Nauk. Ser.Khim., 5, 1222-28 (1996)) describe the synthesis of[2-morpholino-6-nitrobenzopyran]-3-carboxylate. Gupta et al. (Indian J.Chem., 21B, 344-347 (1982)) describe chromene-3-carboxylic acid as anintermediate in the preparation of centrally acting muscle relaxants.Rene and Royer (Eur. J. Med. Chem.—Chim. Ther., 10, 72-78 (1975))describe the preparation of chromene-3-carboxylic acid. U.S. Pat. No.4,665,202, to Rimbault et al., describes 2-phenyl substituted flavenesand thioflavenes as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,250,547,to Lochead et al., describes benzopyran derivatives as 5-lipoxygenaseinhibitors. Satoh et al. [J. Med. Chem., 36, 3580-94 (1993)] describesubstituted chromenes as 5-lipoxygenase inhibitors. U.S. Pat. No.5,155,130, to Stanton et al. describes substituted chromenes as5-lipoxygenase inhibitors, and specifically6-benzyloxy-2H-benzopyran-3-carboxylic acid as an intermediate.

[0012] However, compounds of the current invention have not beendescribed as antiinflammatory cyclooxygenase inhibitors.

DESCRIPTION OF THE INVENTION

[0013] A class of compounds useful in treating cyclooxygenase-2medicated disorders is defined by Formula I″:

[0014] wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);

[0015] wherein R^(a) is selected, from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, acyl and carboxy-C₁-C₆-alkyl;

[0016] wherein each of R^(b) and R^(c) is independently selected fromhydrido, C₁-C3-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C3-alkyl; orwherein CR^(b)R^(c) forms a 3-6 membered cycloalkyl ring;

[0017] wherein R is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl;

[0018] wherein R″ is selected from hydrido, phenyl, thienyl, C₁-C₆-alkyland C₂-C₆-alkenyl;

[0019] wherein R¹ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;

[0020] wherein R² is one or more radicals independently selected fromhydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C6-alkoxy-C₁-C₁-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₁-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyloptionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and

[0021] wherein the A ring atoms A¹, A², A³ and A⁴ are independentlyselected from carbon and nitrogen with the proviso that at least two ofA¹, A², A³ and A⁴ are carbon;

[0022] or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl;

[0023] or an isomer or pharmaceutically acceptable salt thereof.

[0024] A related class of compounds useful in treating cyclooxygenase-2medicated disorders is defined by Formula I′:

[0025] wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);

[0026] wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, alkylsulfonyl, phenylsulfonyl,benzylsulfonyl, acyl and carboxy-C₁-C₆-alkyl;

[0027] wherein each of R^(b) and R^(c) is independently selected fromhydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;

[0028] or wherein CR^(c)R^(b) form a cyclopropyl ring;

[0029] wherein R is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl;

[0030] wherein R″ is selected from hydrido, phenyl, thienyl,C₂-C₆-alkynyl and C₂-C₆-alkenyl;

[0031] wherein R¹ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;

[0032] wherein R²is one or more radicals independently selected fromhydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, —O(CF₂)₂O—, aryloxy, arylthio, arylsulfinyl,heteroaryloxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and

[0033] wherein the A ring atoms A¹, A², A³ and A⁴ are independentlyselected from carbon and nitrogen with the proviso that at least two ofA¹, A², A³ and A⁴ are carbon;

[0034] or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl;

[0035] or an isomer or pharmaceutically acceptable salt thereof.

[0036] A related class of compounds useful in treating cyclooxygenase-2medicated disorders is defined by Formula I:

[0037] wherein X is selected from O or S or NR^(a);

[0038] wherein R^(a) is alkyl;

[0039] wherein R is selected from carboxyl, aminocarbonyl,alkylsulfonylaminocarbonyl and alkoxycarbonyl;

[0040] wherein R¹ is selected from haloalkyl, alkyl, aralkyl, cycloalkyland aryl optionally substituted with one or more radicals selected fromalkylthio, nitro and alkylsulfonyl; and

[0041] wherein R²is one or more radicals selected from hydrido, halo,alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino,aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino,aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,heteroarylaminosulfonyl, aralkylaminosulfonyl,heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, andalkylcarbonyl;

[0042] or wherein R² together with ring A forms a naphthyl radical;

[0043] or an isomer or pharmaceutically acceptable salt thereof.

[0044] Compounds of the present invention would be useful for, but notlimited to, the treatment of inflammation in a subject, and fortreatment of other cyclooxygenase-2 mediated disorders, such as, as ananalgesic in the treatment of pain and headaches, or as an antipyreticfor the treatment of fever. For example, compounds of the inventionwould be useful to treat arthritis, including but not limited torheumatoid arthritis, spondyloarthropathies, gouty arthritis,osteoarthritis, systemic lupus erythematosus and juvenile arthritis.Such compounds of the invention would be useful in the treatment ofasthma, bronchitis, menstrual cramps, preterm labor, tendinitis,bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosisincluding HIV induced apoptosis, lumbago, liver disease includinghepatitis, skin-related conditions such as psoriasis, eczema, acne, UVdamage, burns and dermatitis, and from post-operative inflammationincluding from ophthalmic surgery such as cataract surgery andrefractive surgery. Compounds of the invention also would be useful totreat gastrointestinal conditions such as inflammatory bowel disease,Crohn's disease, gastritis, irritable bowel syndrome and ulcerativecolitis. Compounds of the invention would be useful in treatinginflammation in such diseases as migraine headaches, periarteritisnodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma,rheumatic fever, type I diabetes, neuromuscular junction diseaseincluding myasthenia gravis, white matter disease including multiplesclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury including brain edema, myocardial ischemia, andthe like. The compounds would also be useful in the treatment ofophthalmic diseases, such as retinitis, conjunctivitis, retinopathies,uveitis, ocular photophobia, and of acute injury to the eye tissue. Thecompounds would also be useful in the treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis, and in bone reorption such as associated with osteoporosis.

[0045] The compounds would also be useful for the treatment of certaincentral nervous system disorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and central nervous systemdamage resulting from stroke, ischemia and trauma. The term “treatment”includes partial or total inhibition of the dementia, includingAlzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, and senile dementia.

[0046] The compounds of the invention are useful as anti-inflammatoryagents, such as for the treatment of arthritis, with the additionalbenefit of having significantly less harmful side effects. Thesecompounds would also be useful in the treatment of allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome, and liverdisease. The compounds would also be useful in the treatment of pain,but not limited to postoperative pain, dental pain, muscular pain, andpain resulting from cancer.

[0047] The method above would be useful for, but not limited to,treating and preventing inflammation-related cardiovascular disorders ina subject. The method would be useful for treatment and prevention ofvascular diseases, coronary artery disease, aneurysm, vascularrejection, arteriosclerosis, atherosclerosis including cardiactransplant atherosclerosis, myocardial infarction, embolism, stroke,thrombosis, including venous thrombosis, angina including unstableangina, coronary plaque inflammation, bacterial-induced inflammationincluding Chlamydia-induced inflammation, viral induced inflammation,and inflammation associated with surgical procedures such as vasculargrafting including coronary artery bypass surgery, revascularizationprocedures including angioplasty, stent placement, endarterectomy, orother invasive procedures involving arteries, veins and capillaries.

[0048] The compounds would be useful for, but not limited to, thetreatment of angiogenesis-related disorders in a subject. According tothe present invention, the compounds can be administered to a subject inneed of angiogenesis inhibition. The method would be useful fortreatment of neoplasia, including metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, macular degeneration, retrolentalfibroplasia and neovascular glaucoma; ulcerative diseases such asgastric ulcer; pathological, but non-malignant, conditions such ashemangiomas, including invantile hemaginomas, angiofibroma of thenasopharynx and avascular necrosis of bone; and disorders of the femalereproductive system such as endometriosis.

[0049] Compounds of the invention would be useful for the prevention ortreatment of benign and malignant tumors/neoplasia including cancer,such as colorectal cancer, brain cancer, bone cancer, epithelialcell-derived neoplasia (epithelial carcinoma) such as basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarycancer, cervical cancer, lung cancer, breast cancer and skin cancer,such as squamus cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body. Preferably, neoplasia is selected fromgastrointestinal cancer, Barrett's esophagus, liver cancer, bladdercancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer,lung cancer, breast cancer and skin cancer, such as squamus cell andbasal cell cancers. The compounds can also be used to treat the fibrosiswhich occurs with radiation therapy. The method can be used to treatsubjects having adenomatous polyps, including those with familialadenomatous polyposis (FAP). Additionally, the method can be used toprevent polyps from forming in patients at risk of FAP.

[0050] The administration of compounds of the present invention may beused alone or in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of neoplasia.Alternatively, the compounds described herein may be used in conjunctivetherapy. By way of example, the compounds may be administered alone orin conjunction with other antineoplastic agents or other growthinhibiting agents or other drugs or nutrients.

[0051] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which could be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.Alternatively, other anti-neoplastic agents, such as metallomatrixproteases (MMP), SOD mimics or α_(v)β₃ inhibitors may be used.

[0052] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from the group consisting of5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

[0053] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

[0054] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

[0055] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA², antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532,- Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

[0056] Examples of radioprotective agents which may be used incombination with compounds of the present invention are AD-5, adchnon,amifostine analogues, detox, dimesna, 1-102, MM-159,N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine,WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxidedismutase (Chiron) and superoxide dismutase Enzon.

[0057] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0058] The present compounds may also be used in co-therapies, partiallyor completely, in addition to other antiinflammatories, such as togetherwith steroids, NSAIDs, iNOS inhibitors, p-38 inhibitors, TNF inhibitors,5-lipoxygenase inhibitors, LTB₄ receptor antagonists and LTA₄ hydrolaseinhibitors.

[0059] Suitable LTA₄ hydrolase inhibitors include RP-64966,(S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester(Scripps Res. Inst.),N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic acid (Rhone-PoulencRorer), and 3-(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle).

[0060] Suitable LTB₄ receptor antagonists include, among others,ebselen, linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP, Terumocompound TMK-688, Tanabe compound T-0757, Lilly compounds LY-213024,LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and292728, ONO compounds ONO-LB457, ONO-4057, and ONO-LB-448, Shionogicompound S-2474, calcitrol, Lilly compounds Searle compounds SC-53228,SC-41930, SC-50605 and SC-51146, Warner Lambert compound BPC 15,SmithKline Beecham compound SB-209247 and SK&F compound SKF-104493.Preferably, the LTB₄ receptor antagonists are selected from calcitrol,ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmarkcompound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, andTerumo compound TMK-688.

[0061] Suitable 5-LO inhibitors include, among others, Abbott compoundsA-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, EisaiE-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000,Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen,linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate, and bunaprolast.

[0062] The present compounds may also be used in combination therapieswith opioids and other analgesics, including narcotic analgesics, Mureceptor antagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, Substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. More preferred would be combinations with compounds selectedfrom morphine, meperidine, codeine, pentazocine, buprenorphine,butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone,Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180,HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631,Tramadol [(−) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC_(3742,)SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.

[0063] The compounds can be used in co-therapies, in place of otherconventional antiinflammatories, in combination with one or moreantihistamines, decongestants, diuretics, antitussive agents or withother agents previously known to be effective in combination withantiinflammatory agents.

[0064] The term “prevention” includes either preventing the onset ofclinically evident cardiovascular disorders altogether or preventing theonset of a preclinically evident stage of cardiovascular disorder inindividuals. This includes prophylactic treatment of those at risk ofdeveloping a disease, such as a cardiovascular disorder, dementia orcancer, for example.

[0065] The phrase “therapeutically-effective” is intended to qualify theamount of each agent which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

[0066] The present invention preferably includes compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably,the compounds have a cyclooxygenase-2 IC₅₀ of less than about 0.5 μM,and also have a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase-1IC₅₀ of greater than about 5 μM. Such preferred selectivity may indicatean ability to reduce the incidence of common NSAID-induced side effects.

[0067] A preferred class of compounds consists of those compounds ofFormula I wherein X is oxygen or sulfur; wherein R is selected fromcarboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; whereinR¹ is selected from lower haloalkyl, lower cycloalkyl and phenyl; andwherein R² is one or more radicals selected from hydrido, halo, loweralkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, loweralkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- or6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-or 6-membered nitrogen containing heterocyclosulfonyl, loweralkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, andlower alkylcarbonyl; or wherein R² together with ring A forms a naphthylradical; or an isomer or pharmaceutically acceptable salt thereof.

[0068] A more preferred class of compounds consists of those compoundsof Formula I wherein X is oxygen or sulfur; wherein R is selected fromcarboxyl; wherein R¹ is selected from lower haloalkyl; and wherein R² isone or more radicals selected from hydrido, halo, lower alkyl, lowerhaloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl,lower alkylaminosulfonyl, 5- or 6-membered heteroarylalkylaminosulfonyl,lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogencontaining heterocyclosulfonyl, optionally substituted phenyl, loweraralkylcarbonyl, and lower alkylcarbonyl; or wherein R² together withring A forms a naphthyl radical; or an isomer or pharmaceuticallyacceptable salt thereof.

[0069] An even more preferred class of compounds consists of thosecompounds of Formula I wherein R is carboxyl; wherein R¹ is selectedfrom fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl,dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; andwherein R² is one or more radicals selected from hydrido, chloro,fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl,isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy,trifluoromethyl, difluoromethyl, trifluoromethoxy, amino,N,N-dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl,N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro,N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl,N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl,N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl,N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl,2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R²together with ring A forms a naphthyl radical; or an isomer orpharmaceutically acceptable salt thereof.

[0070] An even more preferred class of compounds consists of thosecompounds of Formula I wherein R is carboxyl; wherein R¹ istrifluoromethyl or pentafluorethyl; and wherein R² is selected from oneor more radicals hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl,isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy,N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl,N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl,N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl,dimethylaminosulfonyl, 2-methylpropylaminosulfonyl,N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; orwherein R² together with ring A forms a naphthyl radical; or an isomeror pharmaceutically acceptable salt thereof.

[0071] A preferred class of compounds consists of those compounds ofFormula I′ wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, acyl and carboxy-C₁-C₆-alkyl; whereineach of R^(b) and R^(b) is independently selected from hydrido,C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;wherein R is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl; wherein R′ isselected from hydrido, phenyl, thienyl and C₂-C₆-alkenyl; wherein R¹ isselected from C₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio,C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; wherein R² is one ormore radicals independently selected from hydrido, halo, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl,aryl-C₂-C₆-alkynyl, aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy,C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl,heteroaryloxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl, C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.

[0072] A more preferred class of compounds consists of those compoundsof Formula I′ wherein X is selected from O, S and NR^(a); wherein R^(a)is selected from hydrido, C₁-C₃-alkyl and (optionally substitutedphenyl)methyl; wherein R′ is selected from hydrido and C₂-C₆-alkenyl;wherein R is carboxyl; wherein R¹ is selected from C₁-C₃-perfluoroalkyl;wherein R²is one or more radicals independently selected from hydrido,halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl,phenyl-C₁-C₆-alkyl, phenyl-C₂-C₆-alkynyl, phenyl-C₂-C₁-alkenyl,C₁-C₃-alkoxy, methylenedioxy, C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio,C₁-C₃-alkylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,C₁-C₃-haloalkyl-C₁-C₃-hydroxyalkyl, phenyl-C₁-C₃-alkyloxy-C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, C₁-C₃-haloalkylthio,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, hydroxyimino-C₁-C₃-alkyl,C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, phenyl-C₁-C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁-C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

[0073] An even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is selected from O, S and NR^(a);wherein R^(a) is selected from hydrido, methyl, ethyl,(4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl, (4-methoxy)benzyl,and (4-cyano)benzyl, (4-nitro)benzyl; wherein R is carboxyl; wherein R′is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein R² is one or more radicalsindependently selected from hydrido, chloro, bromo, fluoro, iodo,methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.

[0074] Within Formula I′ there is a subclass of chromene compoundswherein X is O; wherein R is carboxyl; wherein R″ is selected fromhydrido and C₂-C₆-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl; wherein R² is one or more radicals independentlyselected from hydrido, halo, C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl,phenyl-C₂-C₆-alkynyl, phenyl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, phenyloxy, 5-or 6-membered heteroaryloxy, phenyl-C₁-C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁-C₆-alkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,N-(C₁-C₆-alkyl) amino, N,N-di-(C₁-C₆-alkyl)amino, N-phenylamino,N-(phenyl-C₁-C₆-alkyl)amino, N-heteroarylamino,N-(heteroaryl-C₁-C₆-alkylamino, nitro, amino, aminosulfonyl,N-(C₁-C₆-alkyl)aminosulfonyl, N,N-di-(C₁-C₆-alkyl)aminosulfonyl,N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁-C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

[0075] An even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is O; wherein R is carboxyl; whereinR″ is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein R² is one or more radicalsindependently selected from hydrido, chloro, bromo, fluoro, iodo,methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; and wherein one of the A ring atoms A¹, A², A³ and A⁴ isnitrogen and the other three are carbon; or an isomer orpharmaceutically acceptable salt thereof.

[0076] Another even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is O; wherein R is carboxyl; whereinR″ is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein R² is one or more radicalsindependently selected from hydrido, chloro, bromo, fluoro, iodo,methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, tenzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

[0077] Within Formula I′ there is another subclass of benzothiopyrancompounds wherein X is S; wherein R is carboxyl; wherein R¹ is selectedfrom C₁-C₃-perfluoroalkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl,phenyl-C₁-C₆-alkyl, phenyl-C₂-C₆-alkynyl, phenyl-C₂-C₆-alkenyl,C₁-C₆-alkoxy, phenyloxy, 5- or 6-membered heteroaryloxy,phenyl-C₁-C₆-alkyloxy, 5- or 6-membered heteroaryl-C₁-C₆-alkyloxy,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-alkylamino, N-phenylamino,N-(phenyl-C₁-C₆-alkyl)amino, N-heteroarylamino,N-(heteroaryl-C₁-C₆-alkylamino, nitro, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁-C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

[0078] An even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is S; wherein R is carboxyl; whereinR″ is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein R² is one or more radicalsindependently selected from hydrido, chloro, bromo, fluoro, iodo,methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl,,andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

[0079] Within Formula I′ there is a third subclass of dihydroquinolinecompounds wherein X is NR^(a); wherein R^(a) is selected from hydrido,C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, acyl and carboxy-C₁-C₃-alkyl; wherein Ris carboxyl; wherein R¹ is selected from C₁-C₃-perfluoroalkyl; whereinR² is one or more radicals independently selected from hydrido, halo,C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, phenyl-C₂-C₆-alkynyl,phenyl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, phenyloxy, 5- or 6-memberedheteroaryloxy, phenyl-C₁-C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁-C₆-alkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,C₁-C₆-alkylamino, N-phenylamino, N-(phenyl-C₁-C₆-alkyl)amino,N-heteroarylamino, N-(heteroaryl-C₁-C₆-alkylamino, nitro, amino,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl,N-heteroarylaminosulfonyl, N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁-C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

[0080] An even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is NR^(a); wherein R^(a) is selectedfrom hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, (4-cyano)benzyl, and(4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected fromhydrido and ethenyl; wherein R¹ is selected from trifluoromethyl andpentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

[0081] Within Formula I′ there is a fourth subclass of compounds whereinX is selected from O, S and NR^(a); wherein R^(a) is selected fromhydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, acyl and carboxy-C₁-C₃-alkyl;wherein R is selected from carboxyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl; wherein the A ring atoms A¹, A², A³ and A⁴ areindependently selected from carbon and nitrogen with the proviso that atleast three of A¹, A², A³ and A⁴ are carbon; and wherein R² togetherwith ring A forms a naphthyl or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

[0082] An even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is selected from O, S and NR^(a);wherein R^(a) is selected from hydrido, methyl, ethyl,(4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl, (4-methoxy)benzyl,and (4-cyano)benzyl, (4-nitro)benzyl; wherein R is carboxyl; wherein R′is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or whereinR² together with ring A forms a naphthyl, or quinolyl radical; or anisomer or pharmaceutically acceptable salt thereof.

[0083] A preferred class of compounds consists of those compounds ofFormula I″ wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);wherein R^(a) is selected from hydrido, C₁-C₃-alkyl, (optionallysubstituted phenyl)-C₁-C₃-alkyl, acyl and carboxy-C₁-C₆-alkyl; whereineach of R^(b) and R^(c) is independently selected from hydrido,C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; orwherein CR^(b)R^(c) forms a cyclopropyl ring; wherein R is selected fromcarboxyl, aminocarbonyl, C₁-C₆-alkylsulfonylaminocarbonyl andC₁-C₆-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl, C₁-C₄-alkyl and C₂-C₄-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.

[0084] A more preferred class of compounds of Formula I″ consists ofcompounds wherein X is selected from O, S and NR^(a); wherein R^(a) isselected from hydrido, C₁-C₃-alkyl and (optionally substitutedphenyl)methyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, C₁-C₃-alkyl and C₂-C₃-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl; wherein R² is one or more radicals independentlyselected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,halo-C₂-C₆-alkynyl, optionally substituted phenyl-C₁-C₆-alkyl,optionally substituted phenyl-C₂-C₆-alkynyl, phenyl-C₁-C₆-alkenyl,C₁-C₃-alkoxy, methylenedioxy, C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio,C₁-C₃-alkylsulfinyl, optionally substituted phenyloxy, optionallysubstituted phenylthio, optionally substituted phenylsulfinyl,C₁-C₃-haloalkyl-C₁-C₃-hydroxyalkyl, phenyl-C₁-C₃-alkyloxy-C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, C₁-C₃-haloalkylthio,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, hydroxyimino-C₁-C₃-alkyl,C₁-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, phenyl-C₁-C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁-C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

[0085] An even more preferred class of compounds of Formula I″ consistsof compounds wherein X is selected from O, S and NR^(a); wherein R^(a)is selected from hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl,(4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, ethyl and ethenyl; wherein R¹ is selected from trifluoromethyland pentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.

[0086] Within Formula I there is a subclass of compounds of highinterest represented by Formula II:

[0087] wherein X is selected from O, NR^(a) and S;

[0088] wherein R² is lower haloalkyl;

[0089] wherein R³ is selected from hydrido, and halo;

[0090] wherein R⁴ is selected from hydrido, halo, lower alkyl, lowerhaloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkynyl, phenyl-lower alkynyl, loweralkylaminosulfonyl, lower aralkylaminosulfonyl, lowerheteroaralkylaminosulfonyl, and 5- or 6-membered nitrogen containingheterocyclosulfonyl;

[0091] wherein R⁵ is selected from hydrido, lower alkyl, lowerhydroxyalkyl, halo, lower alkenyl, lower alkynyl, lower alkoxy,phenyloxy, and aryl; and

[0092] wherein R⁶ is selected from hydrido, halo, lower alkyl, loweralkoxy, and aryl;

[0093] or an isomer or pharmaceutically acceptable salt thereof.

[0094] A class of compounds of particular interest consists of thosecompounds of Formula II wherein R² is trifluoromethyl orpentafluoroethyl; wherein R³ is selected from hydrido, chloro, andfluoro; wherein R⁴ is selected from hydrido, chloro, bromo, fluoro,iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, ethynyl,phenylethynyl, benzylcarbonyl, dimethylaminosulfonyl,isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl,phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, andmorpholinosulfonyl; wherein R⁵ is selected from hydrido, methyl, ethyl,isopropyl, tert-butyl, chloro, methoxy, diethylamino, ethynyl, ethenyl,2-hydroxy-1,1-dimethylethyl, phenyloxy and phenyl; and wherein R⁶ isselected from hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl,methoxy, and phenyl; or an isomer or pharmaceutically acceptable saltthereof.

[0095] Within Formula I there is a subclass of compounds of highinterest represented by Formula IIa:

[0096] wherein R³ is selected from hydrido, C₁-C₃-alkyl,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and halo;

[0097] wherein R⁴ is selected from hydrido, halo, C₁-C₄-alkyl,C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₁-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₁-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclosulfonyl; wherein R⁵ isselected from hydrido, C₁-C₃-alkyl, halo, C₁-C₃-haloalkyl,C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl, C₁-C₃-alkoxy, phenoxy,phenoxy independently substituted with one or more radicals selectedfrom C₁-C₃-haloalkyl, nitro, carboxy, C₁-C₃-haloalkoxy, C₁-C₃-alkoxy,cyano, C₁-C₃-alkyl and halo, naphthyloxy, naphthyloxy substituted withone or more halo radicals, phenylthio, phenylthio substituted with oneor more halo radicals, phenylsulfinyl, phenylsulfinyl substituted withone or more halo radicals, phenylsulfonyl, phenylsulfonyl substitutedwith one or more halo radicals, pyridinyloxy, pyridinyloxy substitutedwith one or more halo radicals, and phenyl; and wherein R⁶ is selectedfrom hydrido, halo, cyano, hydroxyiminomethyl, C₁-C₃-hydroxyalkyl,C₂-C₃-alkynyl, phenyl-C₂-C₃-alkynyl, C₁-C₃-alkyl, C₁-C₃-alkoxy, formyland phenyl;

[0098] or an isomer or pharmaceutically acceptable salt thereof.

[0099] A class of compounds of particular interest consists of thosecompounds of Formula IIa wherein R³ is selected from hydrido, andchloro; wherein R⁴ is selected from chloro, methyl, tert-butyl,methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylthio, trifluoromethoxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl,2,2,2-trifluoroethoxy, 2-hydroxy-1,1-dimethylethyl, phenoxy,4-methoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 2-chlorophenoxy,4-cyanophenoxy, 2,6-dimethylphenoxy, 2,4-dichlorophenoxy,3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶ is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, and substituted or unsubstituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.

[0100] A class of compounds of more particular interest consists ofthose compounds of Formula IIa wherein R³ is hydrido; wherein R⁴ ischloro or hydrido; and wherein R⁶ is hydrido; or an isomer orpharmaceutically acceptable salt thereof.

[0101] An even more preferred class of compounds of Formula IIa consistsof compounds wherein R⁵ is selected from 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, and (2-pyridinyl)oxy; or anisomer or pharmaceutically acceptable salt thereof.

[0102] Within Formula I there is a subclass of compounds of highinterest represented by Formula IIb

[0103] wherein R³ is selected from hydrido, lower alkyl, lowerhydroxyalkyl, lower alkoxy and halo;

[0104] wherein R⁴ is selected from hydrido, halo, lower alkyl, loweralkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl,lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl,cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl,lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-memberedheteroaryl, lower hydrooxyalkyl, optionally substituted phenyl and 5- or6-membered nitrogen containing heterocyclosulfonyl;

[0105] wherein R⁵ is selected from hydrido, lower alkyl, halo, lowerhaloalkyl, lower alkoxy, and phenyl; and

[0106] wherein R⁶ is selected from hydrido, halo, cyano,hydrooxyiminomethyl, lower hydroxyalkyl, lower alkynyl, phenylalkynyl,lower alkyl, lower alkoxy, formyl and phenyl;

[0107] or an isomer or pharmaceutically acceptable salt thereof.

[0108] A class of compounds of particular interest consists of thosecompounds of Formula IIb wherein R³ is selected from hydrido, andchloro; wherein R⁴ is selected from chloro, methyl, tert-butyl,methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylsulfide, trifluoromethooxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; andwherein R⁶ is selected from hydrido, chloro, thienyl,hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, andsubstituted or unsubstituted phenyl; or an isomer or pharmaceuticallyacceptable salt thereof.

[0109] Within Formula I there is a subclass of compounds of highinterest represented by Formula IIc:

[0110] wherein R^(a) is selected from hydrido and lower aralkyl;

[0111] wherein R³ is selected from hydrido, lower alkyl, lowerhydroxyalkyl, lower alkoxy and halo;

[0112] wherein R⁴ is selected from hydrido, halo, lower alkyl, loweralkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl,lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl,cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl,lower haloalkoxy, lower alkoxy, lower alkynyl, phenyl-lower alkynyl,lower aralkylcarbonyl, lower dialkylaminosulfonyl, loweralkylaminosulfonyl, lower aralkylaminosulfonyl, lowerheteroaralkylaminosulfonyl, 5- or 6-membered heteroaryl, lowerhydroxyalkyl, optionally substituted phenyl and 5- or 6-memberednitrogen containing heterocyclosulfonyl;

[0113] wherein R⁵ is selected from hydrido, lower alkyl, halo, lowerhaloalkyl, lower alkoxy, and phenyl; and

[0114] wherein R⁶ is selected from hydrido, halo, cyano,hydroxyiminomethyl, lower hydroxyalkyl, lower alkynyl, phenylalkynyl,lower alkyl, lower alkoxy, formyl and phenyl;

[0115] or an isomer or pharmaceutically acceptable salt thereof.

[0116] A class of compounds of particular interest consists of thosecompounds of Formula IIc wherein R³ is selected from hydrido, andchloro; wherein R⁴ is selected from chloro, methyl, tert-butyl,methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylsulfide, trifluoromethoxy, ethynyl, phenylethynyl,substituted or unsubstituted phenylcarbonyl, and substituted orunsubstituted phenyl; wherein R⁵ is selected from hydrido, methyl,tert-butyl, chloro; and wherein R⁶ is selected from hydrido, chloro,thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl,and substituted or unsubstituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.

[0117] A class of compounds of more particular interest consists ofthose compounds of Formula IIc wherein R³ is hydrido or chloro; whereinR⁴ is selected from ethynyl, and optionally substituted phenylethynyl;or an isomer or pharmaceutically acceptable salt thereof.

[0118] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptable saltsthereof as follows:

[0119]6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0120]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thiol-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0121]6-chloro-1,2-dihydro-7-[(2-pyridyl-N-oxide)oxyl-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0122]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-1,2-dihydro-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0123]6-chloro-1,2-dihydro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0124]6-chloro-7-((3-chloro-2-pyridyl-{N-oxide})thio)-1,2-dihydro-2-(trifluoromethyl)-2H-quinoline-3-carboxylicacid;

[0125]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0126]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0127]6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0128]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0129]6-chloro-7-(3,4-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0130]6-chloro-7-(3-bromo-4-chlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0131]6-chloro-7-(4-bromo-3-chlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0132]6-chloro-7-(3,4-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0133]6-chloro-7-[4-chloro-3-(trifluoromethyl)phenoxyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0134]6-chloro-7-[3-chloro-4-(trifluoromethyl)phenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0135]6-chloro-7-(2,6-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0136]6-chloro-7-(2,6-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0137]6-chloro-7-(2,6-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0138]6-chloro-7-(2,5-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0139]6-chloro-7-(2,5-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0140]6-chloro-7-(2,5-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0141]6-chloro-7-(2,3-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0142]6-chloro-7-(2,3-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0143]6-chloro-7-(2,3-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0144]6-chloro-7-(4-chloro-3-cyanophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0145]6-chloro-7-(3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0146]6-chloro-7-(2-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0147]6-chloro-7-(4-chloro-3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0148]6-chloro-7-(4-chloro-2-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0149] 6-chloro-7-(2-chloro-3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0150] 7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0151]6-chloro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0152]6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0153]7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;

[0154] 6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0155]6-chloro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0156]6-chloro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0157]6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0158]6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0159]6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0160]6-chloro-7-(4-cyanophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0161]6-chloro-7-[4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0162]6-chloro-7-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0163]6-chloro-7-(2-bromo-4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0164]6-chloro-7-f(6-bromo-2-naphthyl)oxyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0165]6-chloro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0166]6-chloro-7-[(4-methoxyphenyl)thiol-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0167]6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0168]6-chloro-7-[(4-chlorophenyl)sulfinyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0169]6-chloro-7-[(4-chlorophenyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0170]6-chloro-7-phenylthio-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0171]6-chloro-7-(3-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0172]6-chloro-7-(2,4-dichlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0173]6-chloro-7-(3,4-difluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0174]6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0175]6-chloro-7-((2-chloro-3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0176]6-chloro-7-[(3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0177]6-chloro-7-[(2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0178]6-chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0179]6-chloro-7-(2-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0180]6-chloro-7-(4-chloro-3-fluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0181]6-chloro-7-(4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0182]6-chloro-7-(2-chloro-4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0183]6-chloro-7-(3-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0184]6-chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0185]6-chloro-1,2-dihydro-8-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0186] 1,2-dihydro-5-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0187]1,2-dihydro-6-(4-fluorophenyl)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0188] 1,2-dihydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0189]8-bromo-1,2-dihydro-6-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0190]1,2-dihydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0191]6-chloro-7-[(3-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0192]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0193]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0194]6-chloro-7-[(4-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0195]6-chloro-7-[(5-chloro-2-pyridyl-(N-oxide))oxyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0196]6-chloro-7-((6-chloro-2-pyridyl-(N-oxide})oxyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0197] 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0198] 7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0199] 7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0200] 2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0201] 7-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0202] 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0203] 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0204]6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0205]6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0206] 2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0207] 8-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0208]7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0209] 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0210] 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0211] 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0212] 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0213] 8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0214] 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0215] 7,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0216] 7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0217] 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0218] 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0219]6,8-bis(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0220] 7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0221] 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0222] 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0223] 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0224] 8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0225] 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0226] 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0227] 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0228] 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0229] 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0230] 6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0231] 6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0232] 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0233] ethyl 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate;

[0234] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0235] 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0236] 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0237] 6,8-difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0238] 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0239] 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0240] 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0241] 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0242] 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0243] 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0244]7-(N,N-diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0245]6-[[(phenylmethyl)amino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0246]6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0247] 6-aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0248]6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0249]6-[(4-morpholino)sulfonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0250]6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0251]6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0252] 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0253]8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0254]6-N,N-diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0255] 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0256]6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0257]6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0258] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;

[0259]6-[[(2-furanylmethyl)amino)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0260]6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0261] 6-[(phenylethyl) amino)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0262] 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0263] 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0264] 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0265] 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0266]6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0267]6-bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0268] 5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0269] 6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0270] 6-hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0271]6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0272] 2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0273] 5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0274] 6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0275] 6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0276]6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0277] 5,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0278]6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0279]6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0280]2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylicacid;

[0281]6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0282] 6-chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0283] 5-methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0284] 6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0285]6-(4-chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0286]6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0287] 6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0288]8-chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0289]2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid;

[0290]6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0291]6-(3-chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0292]6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0293]8-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid;

[0294] 6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0295]6-chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0296]6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0297]8-(1H-benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0298]7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid;

[0299]6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0300]6-chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0301]6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0302]6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0303]6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0304]6-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0305]6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0306]6-chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0307]6-chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0308]6-chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0309]6-chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0310]6-chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0311]6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0312]6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0313]6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0314]6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0315]6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0316]6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0317] 6-bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0318]6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0319] 6-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0320]8-chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0321] 6,8-diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0322]6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0323] 6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0324]6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0325]6-(4-bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0326] 6-(ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0327] 6-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0328]6-chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0329]6-chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylicacid;

[0330]6-chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic acid;

[0331]6-chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0332]6-(2,2,2-trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0333] 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0334] 6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0335]6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0336] 7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0337] 6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0338] 8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0339] 2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;

[0340]6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0341] 7-chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0342] 6,7-dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0343]2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylicacid;

[0344] 6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0345] 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0346]6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;

[0347]6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;

[0348] 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0349] 6-bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0350]6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0351] 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0352]6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0353]6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid;

[0354]6-chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0355]6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid;

[0356]6-chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0357]6-chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0358]6-chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0359]6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid;

[0360]6-chloro-7-[(3-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0361]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0362]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0363]6-chloro-7-[(4-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0364]6-chloro-7-[(5-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0365]6-chloro-7-[(6-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0366]6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0367]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0368]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-dihydroquinoline-3-carboxylicacid;

[0369]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-dihydroquinoline-3-carboxylicacid;

[0370]6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-dihydroquinoline-3-carboxylicacid;

[0371]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1-dihydroquinoline-3-carboxylicacid;

[0372]6-chloro-7-[(2-pyridyl-N-oxide)oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0373]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})oxy]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0374]6-chloro-7-[(2-pyridyl-N-oxide)thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0375]6-chloro-7-[(3-chloro-2-pyridyl-{N-oxide})thio]-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0376] 7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0377]6-chloro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0378]6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0379]7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;

[0380] 6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0381]6-chloro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0382]6-chloro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0383]6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0384]6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0385]6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0386]6-chloro-7-(4-cyanophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0387]6-chloro-7-[4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0388]6-chloro-7-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0389]6-chloro-7-(2-bromo-4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0390]6-chloro-7-[(6-bromo-2-naphthyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0391]6-chloro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0392]6-chloro-7-[(4-methoxyphenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0393]6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0394]6-chloro-7-[(4-chlorophenyl)sulfinyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0395]6-chloro-7-[(4-chlorophenyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0396]6-chloro-7-phenylthio-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0397]6-chloro-7-(3-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0398]6-chloro-7-(2,4-dichlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0399]6-chloro-7-(3,4-difluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0400]6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0401]6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0402]6-chloro-7-[(3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0403]6-chloro-7-[(2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0404]6-chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0405]6-chloro-7-(2-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0406]6-chloro-7-(4-chloro-3-fluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0407]6-chloro-7-(4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0408]6-chloro-7-(2-chloro-4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0409]6-chloro-7-(3-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0410]6-chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0411] 1,2-dihydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0412]1,2-dihydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0413]6-chloro-7-(3,4-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0414]6-chloro-7-(3-bromo-4-chlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0415]6-chloro-7-(4-bromo-3-chlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0416]6-chloro-7-(3,4-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0417]6-chloro-7-[4-chloro-3-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0418]6-chloro-7-[3-chloro-4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0419]6-chloro-7-(2,6-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0420]6-chloro-7-(2,6-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0421]6-chloro-7-(2,6-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0422]6-chloro-7-(2,5-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0423]6-chloro-7-(2,5-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0424]6-chloro-7-(2,5-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0425]6-chloro-7-(2,3-dichlorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0426]6-chloro-7-(2,3-dibromophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0427]6-chloro-7-(2,3-difluorophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0428]6-chloro-7-(4-chloro-3-cyanophenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0429]6-chloro-7-(3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0430]6-chloro-7-(2-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0431]6-chloro-7-(4-chloro-3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0432]6-chloro-7-(4-chloro-2-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0433] 6-chloro-7-(2-chloro-3-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0434] 6-chloro-7-(3-chloro-2-tert-butylphenoxy)2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0435]6-chloro-7-(3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0436]6-chloro-7-(2-chloro-3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0437]6-chloro-7-(4-chloro-3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0438]6-chloro-7-(5-chloro-3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0439]6-chloro-7-(2,5-dichloro-3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0440]6-chloro-7-(2,4-dichloro-3-thienyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0441]6-chloro-7-[(3-chloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0442]6-chloro-7-[(4-chloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0443]6-chloro-7-[(3-chloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0444]6-chloro-7-[(5-chloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0445]6-chloro-7-[(6-chloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0446]6-chloro-7-[(5,6-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0447]6-chloro-7-[(3,4-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0448]6-chloro-7-[(4,5-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0449]6-chloro-7-[(3,5-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0450]6-chloro-7-[(3,6-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0451]6-chloro-7-[(4,5-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0452]6-chloro-7-[(4,6-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0453]6-chloro-7-[(5,6-dichloro-2-pyridyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0454]6-chloro-7-[(2-quinolyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0455] 2-trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid;

[0456] 2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid;

[0457] 2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid;

[0458]5-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylicacid;

[0459]6-(trifluoromethyl)-6h-1,3-dioxolo[4,5-g][1]benzopyran-7-carboxylicacid; and

[0460] 3-(trifluoromethyl)-3H-benzofuro[3,2-f][1]benzopyran-2-carboxylicacid.

[0461] A preferred family of specific compounds of particular interestwithin Formulas I-I″ consists of compounds as follows:

[0462] (S)-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0463](S)-6-chloro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0464](S)-6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0465](S)-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;

[0466](S)-6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0467](S)-6-chloro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0468](S)-6-chloro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0469](S)-6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0470](S)-6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0471](S)-6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0472](S)-6-chloro-7-(4-cyanophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0473](S)-6-chloro-7-[4-(trifluoromethyl)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0474](S)-6-chloro-7-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0475](S)-6-chloro-7-(2-bromo-4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0476](S)-6-chloro-7-[(6-bromo-2-naphthyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0477](S)-6-chloro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0478](S)-6-chloro-7-[(4-methoxyphenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0479](S)-6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0480](S)-6-chloro-7-[(4-chlorophenyl)sulfinyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0481](S)-6-chloro-7-[(4-chlorophenyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0482](S)-6-chloro-7-phenylthio-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0483](S)-6-chloro-7-(3-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0484](S)-6-chloro-7-(2,4-dichlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0485](S)-6-chloro-7-(3,4-difluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0486](S)-6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0487](S)-6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0488](S)-6-chloro-7-[(3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0489](S)-6-chloro-7-[(2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0490](S)-6-chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0491](S)-6-chloro-7-(2-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0492](S)-6-chloro-7-(4-chloro-3-fluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0493](S)-6-chloro-7-(4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0494](S)-6-chloro-7-(2-chloro-4-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0495](S)-6-chloro-7-(3-carboxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0496](S)-6-chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0497](S)-6-chloro-1,2-dihydro-8-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0498](S)-1,2-dihydro-5-methyl-2-(trifluoromethyl)-3-quinolinecarboxylic acid;

[0499](S)-1,2-dihydro-6-(4-fluorophenyl)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0500](S)-1,2-dihydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0501](S)-8-bromo-1,2-dihydro-6-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0502](S)-1,2-dihydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0503] (S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0504] (S)-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0505] (S)-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0506] (S)-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0507] (S)-7-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0508](S)-6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0509](S)-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0510](S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0511](S)-6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0512] (S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0513] (S)-8-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0514](S)-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0515] (S)-6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0516] (S)-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0517](S)-8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0518](S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0519] (S)-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0520] (S)-5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0521] (S)-7,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0522] (S)-7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0523] (S)-8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0524] (S)-7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0525](S)-6,8-bis(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0526] (S)-7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0527](S)-7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0528] (S)-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0529](S)-6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0530] (S)-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0531](S)-6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0532](S)-6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0533] (S)-6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0534] (S)-6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0535] (S)-6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0536] (S)-6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0537] (S)-6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0538] (S)-6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0539] (S)-ethyl6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate;

[0540](S)-6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0541](S)-8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0542](S)-8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0543] (S)-6,8-difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0544](S)-6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0545](S)-8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0546](S)-8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0547](S)-8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0548](S)-6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0549](S)-6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0550](S)-7-(N,N-diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0551](S)-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0552](S)-6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0553](S)-6-aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0554](S)-6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0555](S)-6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0556](S)-6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0557](S)-6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0558](S)-6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0559](S)-8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0560](S)-6-N,N-diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0561] (S)-6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0562](S)-6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0563](S)-6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0564] (S)-6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0565](S)-6-[[(2-furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0566](S)-6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0567](S)-6-[[(phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0568] (S)-6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

[0569](S)-6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0570](S)-8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0571] (S)-6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0572](S)-6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0573](S)-6-bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0574] (S)-5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0575] (S)-6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0576](S)-6-hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0577](S)-6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0578] (S)-2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0579](S)-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0580](S)-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0581](S)-6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0582](S)-6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0583] (S)-5,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0584](S)-6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0585](S)-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0586](S)-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylicacid;

[0587](S)-6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0588](S)-6-chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0589] (S)-5-methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0590] (S)-6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0591](S)-6-(4-chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0592](S)-6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0593] (S)-6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0594](S)-8-chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0595](S)-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid;

[0596](S)-6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0597](S)-6-(3-chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0598](S)-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0599](S)-8-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid;

[0600](S)-6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0601](S)-6-chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0602](S)-6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0603](S)-8-(1H-benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0604](S)-7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid;

[0605](S)-6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0606](S)-6-chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0607](S)-6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0608](S)-6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0609](S)-6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0610](S)-6-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0611](S)-6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0612](S)-6-chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0613](S)-6-chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0614](S)-6-chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0615](S)-6-chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0616](S)-6-chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0617](S)-6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0618](S)-6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0619](S)-6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0620](S)-6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0621](S)-6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0622](S)-6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0623](S)-6-bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0624](S)-6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0625] (S)-6-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0626](S)-8-chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0627] (S)-6,8-diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0628](S)-6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0629](S)-6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;

[0630](S)-6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0631](S)-6-(4-bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0632] (S)-6-(ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0633] (S)-6-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0634](S)-6-chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid;

[0635](S)-6-chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylicacid;

[0636](S)-6-chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylicacid;

[0637](S)-6-chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0638](S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;

[0639] (S)-6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0640](S)-6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0641](S)-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0642] (S)-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0643](S)-6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0644] (S)-8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0645] (S)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;

[0646](S)-6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0647] (S)-7-chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0648](S)-6,7-dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid;

[0649](S)-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylicacid;

[0650](S)-6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid;

[0651](S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;

[0652](S)-6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0653](S)-6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0654] (S)-6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0655] (S)-6-bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0656](S)-1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0657](S)-6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0658] (S)-6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0659](S)-6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0660](S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid;

[0661](S)-6-chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0662](S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid;

[0663](S)-6-chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0664](S)-6-chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0665](S)-6-chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;

[0666](S)-6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid;

[0667] (S)-2-trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid;

[0668] (S)-2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;

[0669] (S)-2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid;and

[0670](S)-5-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylicacid.

[0671] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma hydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where the term “alkyl” isused, either alone or within other terms such as “haloalkyl” and“alkylsulfonyl”, it embraces linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about six carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl and the like. Even more preferred are loweralkyl radicals having one to three carbon atoms. The term “alkenyl”embraces linear or branched radicals having at least one carbon-carbondouble bond of two to about twenty carbon atoms or, preferably, two toabout twelve carbon atoms. More preferred alkenyl radicals are “loweralkenyl” radicals having two to about six carbon atoms. Examples ofalkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The term “alkynyl” denotes linear or branched radicalshaving two to about twenty carbon atoms or, preferably, two to abouttwelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms. Most preferred are loweralkynyl radicals having two to about six carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like. The terms “alkenyl”and “lower alkenyl”, embrace radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. The term“halo” means halogens such as fluorine, chlorine, bromine or iodineatoms. The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl” meansalkyl radicals having all hydrogen atoms replaced with fluoro atoms.Examples include trifluoromethyl and pentafluoroethyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even morepreferred are lower hydroxyalkyl radicals having one to three carbonatoms. The term “cyanoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one cyano radicals. More preferred cyanoalkyl radicals are “lowercyanoalkyl” radicals having one to six carbon atoms and one cyanoradical. Even more preferred are lower cyanoalkyl radicals having one tothree carbon atoms. Examples of such radicals include cyanomethyl. Theterms “alkoxy” embrace linear or branched oxy-containing radicals eachhaving alkyl portions of one to about ten carbon atoms. More preferredalkoxy radicals are “lower alkoxy” radicals having one to six carbonatoms. Examples of such radicals include methoxy, ethoxy, propoxy,butoxy and tert-butoxy. Even more preferred are lower alkoxy radicalshaving one to three carbon atoms. The “alkoxy” radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “haloalkoxy” radicals. Even more preferred are lowerhaloalkoxy radicals having one to three carbon atoms. Examples of suchradicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term “aryl”, aloneor in combination, means a carbocyclic aromatic system containing one ortwo rings wherein such rings may be attached together in a pendentmanner or may be fused. The term “aryl” embraces aromatic radicals suchas phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 to 3 substituentssuch as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy andlower alkylamino. The term “heterocyclyl” embraces saturated, partiallysaturated and unsaturated heteroatom-containing ring-shaped radicals,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturatedheterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl];unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen-atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl] and the like. The term also embraces radicals whereheterocyclic radicals are fused with aryl radicals. Examples of suchfused bicyclic radicals include benzofuran, benzothiophene, and thelike. Said “heterocyclyl” group may have 1 to 3 substituents such aslower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includebenzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl,dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran,benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl,furyl, and pyrazinyl. Even more preferred heteroaryl radicals are 5- or6-membered heteroaryl, containing one or two heteroatoms selected fromsulfur nitrogen and oxygen, selected from thienyl, furanyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyridyl, piperidinyl and pyrazinyl. The term “sulfonyl”, whether usedalone or linked to other terms such as alkylsulfonyl, denotesrespectively divalent radicals —SO₂—. “Alkylsulfonyl” embraces alkylradicals attached to a sulfonyl radical, where alkyl is defined asabove. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl”radicals having one to six carbon atoms. Even more preferred are loweralkylsulfonyl radicals having one to three carbon atoms. Examples ofsuch lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyland propylsulfonyl. “Haloalkylsulfonyl” embraces haloalkyl radicalsattached to a sulfonyl radical, where haloalkyl is defined as above.More preferred haloalkylsulfonyl radicals are “lower haloalkylsulfonyl”radicals having one to six carbon atoms. Even more preferred are lowerhaloalkylsulfonyl radicals having one to three carbon atoms. Examples ofsuch lower haloalkylsulfonyl radicals include trifluoromethylsulfonyl.The term “arylalkylsulfonyl” embraces aryl radicals as defined above,attached to an alkylsulfonyl radical. Examples of such radicals includebenzylsulfonyl and phenylethylsulfonyl. The term “heterocyclosulfonyl”embraces heterocyclo radicals as defined above, attached to a sulfonylradical. More preferred heterocyclosulfonyl radicals contain 5-7membered heterocyclo radicals containing one or two heteroatoms.Examples of such radicals include tetrahydropyrrolylsulfonylmorpholinylsulfonyl and azepinylsulfonyl. The terms “sulfamyl,”“aminosulfonyl” and “sulfonamidyl,” whether alone or used with termssuch as “N-alkylaminosulfonyl”, “N-arylaminosulfonyl”,“N,N-dialkylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl”, denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). The term “alkylaminosulfonyl” includes“N-alkylaminosulfonyl” and “N,N-dialkylaminosulfonyl” where sulfamylradicals are substituted, respectively, with one alkyl radical, or,twoalkyl radicals. More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, N-ethylaminosulfonyl andN-methyl-N-ethylaminosulfonyl. The terms “N-arylaminosulfonyl” and“N-alkyl-N-arylaminosulfonyl” denote sulfamyl radicals substituted,respectively, with one aryl radical, or one alkyl and one aryl radical.More preferred N-alkyl-N-arylaminosulfonyl radicals are “lowerN-alkyl-N-arylsulfonyl” radicals having alkyl radicals of one to sixcarbon atoms. Even more preferred are lower N-alkyl-N-arylsulfonylradicals having one to three carbon atoms. Examples of such lowerN-alkyl-N-aryl-aminosulfonyl radicals includeN-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl.Examples of such N-aryl-aminosulfonyl radicals includeN-phenylaminosulfonyl. The term “arylalkylaminosulfonyl” embracesaralkyl radicals as described above, attached to an aminosulfonylradical. More preferred are lower arylalkylaminosulfonyl radicals havingone to three carbon atoms. The term “heterocyclylaminosulfonyl” embracesheterocyclyl radicals as described above, attached to an aminosulfonylradical. The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H. The term“carboxyalkyl” embraces radicals having a carboxy radical as definedabove, attached to an alkyl radical. The term “carbonyl”, whether usedalone or with other terms, such as “alkylcarbonyl”, denotes —(C═O)—. Theterm “acyl” denotes a radical provided by the residue after removal ofhydroxyl from an organic acid. Examples of such acyl radicals includealkanoyl and aroyl radicals. Examples of such lower alkanoyl radicalsinclude formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term “aroyl”embraces aryl radicals with a carbonyl radical as defined above.Examples of aroyl include benzoyl, naphthoyl, and the like and the arylin said aroyl may be additionally substituted. The term “alkylcarbonyl”embraces radicals having a carbonyl radical substituted with an alkylradical. More preferred alkylcarbonyl radicals are “lower alkylcarbonyl”radicals having one to six carbon atoms. Even more preferred are loweralkylcarbonyl radicals having one to three carbon atoms. Examples ofsuch radicals include methylcarbonyl and ethylcarbonyl. The term“haloalkylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with an haloalkyl radical. More preferred haloalkylcarbonylradicals are “lower haloalkylcarbonyl” radicals having one to six carbonatoms. Even more preferred are lower haloalkylcarbonyl radicals havingone to three carbon atoms. Examples of such radicals includetrifluoromethylcarbonyl. The term “arylcarbonyl” embraces radicalshaving a carbonyl radical substituted with an aryl radical. Morepreferred arylcarbonyl radicals include phenylcarbonyl. The term“heteroarylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with a heteroaryl radical. Even more preferred are 5- or6-membered heteroarylcarbonyl radicals. The term “arylalkylcarbonyl”embraces radicals having a carbonyl radical substituted with anarylalkyl radical. More preferred radicals arephenyl-C₁-C₃-alkylcarbonyl, including benzylcarbonyl. The term“heteroarylalkylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with a heteroarylalkyl radical. Even more preferred arelower heteroarylalkylcarbonyl radicals having 5-6-membered heteroarylradicals attached to alkyl portions having one to three carbon atoms.The term “alkoxycarbonyl” means a radical containing an alkoxy radical,as defined above, attached via an oxygen atom to a carbonyl radical.Preferably, “lower alkoxycarbonyl” embraces alkoxy radicals having oneto six carbon atoms. Examples of such “lower alkoxycarbonyl” esterradicals include substituted or unsubstituted methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonylEven more preferred are lower alkoxycarbonyl radicals having alkoxyportions of one to three carbon atoms. The term “aminocarbonyl” whenused by itself or with other terms such as “aminocarbonylalkyl”,“N-alkylaminocarbonyl”, “N-arylaminocarbonyl”,“N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”,“N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(═O)NH₂. The terms “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have beensubstituted with one alkyl radical and with two alkyl radicals,respectively. More preferred are “lower alkylaminocarbonyl” having loweralkyl radicals as described above attached to an aminocarbonyl radical.The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical. The term “N-cycloalkylaminocarbonyl”denoted aminocarbonyl radicals which have been substituted with at leastone cycloalkyl radical. More preferred are “lowercycloalkylaminocarbonyl” having lower cycloalkyl radicals of three toseven carbon atoms, attached to an aminocarbonyl radical. The term“aminoalkyl” embraces alkyl radicals substituted with amino radicals.The term “alkylaminoalkyl” embraces aminoalkyl radicals having thenitrogen atom substituted with an alkyl radical. Even more preferred arelower alkylaminoalkyl radicals having one to three carbon atoms. Theterm “heterocyclylalkyl” embraces heterocyclic-substituted alkylradicals. More preferred heterocyclylalkyl radicals are “5- or6-membered heteroarylalkyl” radicals having alkyl portions of one to sixcarbon atoms and a 5- or 6-membered heteroaryl radical. Even morepreferred are lower heteroarylalkyl radicals having alkyl portions ofone to three carbon atoms. Examples include such radicals aspyridylmethyl and thienylmethyl. The term “aralkyl” embracesaryl-substituted alkyl radicals. Preferable aralkyl radicals are “loweraralkyl” radicals having aryl radicals attached to alkyl radicals havingone to six carbon atoms. Even more preferred are lower aralkyl radicalsphenyl attached to alkyl portions having one to three carbon atoms.Examples of such radicals include benzyl, diphenylmethyl andphenylethyl. The aryl in said aralkyl may be additionally substitutedwith halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term“arylalkenyl” embraces aryl-substituted alkenyl radicals. Preferablearylalkenyl, radicals are “lower arylalkenyl” radicals having arylradicals attached to alkenyl radicals having two to six carbon atoms.Examples of such radicals include phenylethenyl. The aryl in saidarylalkenyl may be additionally substituted with halo, alkyl, alkoxy,halkoalkyl and haloalkoxy. The term “arylalkynyl” embracesaryl-substituted alkynyl radicals. Preferable arylalkynyl radicals are“lower arylalkynyl” radicals having aryl radicals attached to alkynylradicals having two to six carbon atoms. Examples of such radicalsinclude phenylethynyl. The aryl in said aralkyl may be additionallysubstituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. Theterms benzyl and phenylmethyl are interchangeable. The term “alkylthio”embraces radicals containing a linear or branched alkyl radical, of oneto ten carbon atoms, attached to a divalent sulfur atom. Even morepreferred are lower alkylthio radicals having one to three carbon atoms.An example of “alkylthio” is methylthio, (CH₃—S—). The term“haloalkylthio” embraces radicals containing a haloalkyl radical, of oneto ten carbon atoms, attached to a divalent sulfur atom. Even morepreferred are lower haloalkylthio radicals having one to three carbonatoms. An example of “haloalkylthio” is trifluoromethylthio. The term“alkylsulfinyl” embraces radicals containing a linear or branched alkylradical, of one to ten carbon atoms, attached to a divalent —S(═O)—atom. More preferred are lower alkylsulfinyl radicals having one tothree carbon atoms. The term “arylsulfinyl” embraces radicals containingan aryl radical, attached to a divalent —S(═O)— atom. Even morepreferred are optionally substituted phenylsulfinyl radicals. The term“haloalkylsulfinyl” embraces radicals containing a haloalkyl radical, ofone to ten carbon atoms, attached to a divalent —S(═O)— atom. Even morepreferred are lower haloalkylsulfinyl radicals having one to threecarbon atoms. The terms “N-alkylamino” and “N,N-dialkylamino” denoteamino groups which have been substituted with one alkyl radical and withtwo alkyl radicals, respectively. More preferred alkylamino radicals are“lower alkylamino” radicals having one or two alkyl radicals of one tosix carbon atoms, attached to a nitrogen atom. Even more preferred arelower alkylamino radicals having one to three carbon atoms. Suitable“alkylamino” may be mono or dialkylamino such as N-methylamino,N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term“arylamino” denotes amino groups which have been substituted with one ortwo aryl radicals, such as N-phenylamino. The “arylamino” radicals maybe further substituted on the aryl ring portion of the radical. The term“heteroarylamino” denotes amino groups which have been substituted withone or two heteroaryl radicals, such as N-thienylamino. The“heteroarylamino” radicals may be further substituted on the heteroarylring portion of the radical. The term “aralkylamino” denotes aminogroups which have been substituted with one or two aralkyl radicals.More preferred are phenyl-C₁-C₃-alkylamino radicals, such asN-benzylamino. The “aralkylamino” radicals may be further substituted onthe aryl ring portion of the radical. The terms “N-alkyl-N-arylamino”and “N-aralkyl-N-alkylamino” denote amino groups which have beensubstituted with one aralkyl and one alkyl radical, or one aryl and onealkyl radical, respectively, to an amino group. The term “arylthio”embraces aryl radicals of six to ten carbon atoms, attached to adivalent sulfur atom. An example of “arylthio” is phenylthio. The term“aralkylthio” embraces aralkyl radicals as described above, attached toa divalent sulfur atom. More preferred are phenyl-C₁-C₃-alkylthioradicals. An example of “aralkylthio” is benzylthio. The term“aralkylsulfonyl” embraces aralkyl radicals as described above, attachedto a divalent sulfonyl radical. More preferred arephenyl-C₁-C₃-alkylsulfonyl radicals. The term “aryloxy” embracesoptionally substituted aryl radicals, as defined above, attached to anoxygen atom. Examples of such radicals include phenoxy. The term“aralkoxy” embraces oxy-containing aralkyl radicals attached through anoxygen atom to other radicals. More preferred aralkoxy radicals are“lower aralkoxy” radicals having optionally substituted phenyl radicalsattached to lower alkoxy radical as described above.

[0672] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulaI-I″ in association with at least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0673] The present invention also comprises a method of treatingcyclooxygenase-2 mediated disorders, such as inflammation, in a subject,the method comprising treating the subject having or susceptible to suchdisorder with a therapeutically-effective amount of a compound ofFormula I-I″.

[0674] Also included in the family of compounds of Formula I-I″ are thestereoisomers thereof. Compounds of the present invention can possessone or more asymmetric carbon atoms and are thus capable of existing inthe form of optical isomers as well as in the form of racemic ornonracemic mixtures thereof. Accordingly, some of the compounds of thisinvention may be present in racemic mixtures which are also included inthis invention. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive base and then separation of the mixture of diastereoisomers bycrystallization, followed by liberation of the optically active basesfrom these salts. Examples of appropriate bases are brucine, strychnine,dehydroabietylamine, quinine, cinchonidine, ephedrine,α-methylbenzylamine, amphetamine, deoxyphedrine, chloramphenicolintermediate, 2-amino-1-butanol, and 1-(1-napthyl)ethylamine. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules. The synthesizeddiastereoisomers can be separated by conventional means such aschromatography, distillation, crystallization or sublimation, and thenhydrolyzed to deliver the enantiomerically pure compound. The opticallyactive compounds of Formula I can likewise be obtained by utilizingoptically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt. Additional methods forresolving optical isomers, known to those skilled in the art may beused, for example, those discussed by J. Jaques et al in Enantiomers,Racemates, and Resolutions, John Wiley and Sons, New York (1981).

[0675] Also included in the family of compounds of Formula I-I″ are theprotected acids thereof, such as the esters, hydroxyamino derivatives,amides and sulfonamides. Thus primary and secondary amines can bereacted with the chromene-3-carboxylic acids of Formula I-I″ to formamides which can be useful as prodrugs. Preferred aminesheterocyclicamines, including optionally substituted aminothiazoles,optionally substituted amino-isoxazoles, and optionally substitutedaminopyridines; aniline derivatives; sulfonamides; aminocarboxylicacids; and the like. Additionally, 1-acyldihydroquinolines can behave asprodrugs for the 1H-dihydroquinolines. The esters, hydroxyaminoderivatives and sulfonamides can be prepared from the acids by methodsknown to one skilled in the art.

[0676] Also included in the family of compounds of Formula I-I″ are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-I″ may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicyclic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formula I-I″ include metallic salts,such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases includingprimary, secondary and tertiary amines, substituted amines includingcyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine,N-ethyl morpholine, piperazine, piperidine, triethylamine,trimethylamine. All of these salts may be prepared by conventional meansfrom the corresponding compound of the invention by reacting, forexample, the appropriate acid or base with the compound of Formula I-I″.

[0677] General Synthetic Procedures

[0678] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-16, wherein the R¹-R⁶ substituentsare as defined for Formulas I-II, above, except where further noted.

[0679] Synthetic Scheme 1 illustrates the general method for thepreparation of a wide variety of substituted 2H-1-benzopyran derivatives3 and 4. In step 1, a representative ortho-hydroxybenzaldehyde(salicylaldehyde) derivative 1 is condensed with an acrylate derivative2 in the presence of base, such as potassium carbonate in a solvent suchas dimethylformamide, to afford the desired 2H-1-benzopyran ester 3. Analternative base-solvent combination for this condensation includes anorganic base such as triethylamine and a solvent such as dimethylsulfoxide. In step 2 the ester is hydrolyzed to the corresponding acid,such as by treatment with aqueous base (sodium hydroxide) in a suitablesolvent such as ethanol to afford after acidification the substituted2H-1-benzopyran-3-carboxylic acid 4.

[0680] Synthetic Scheme 2 shows the general method for functionalizingselected 2H-1-benzopyrans. Treatment of the 2H-1-benzopyran carboxylicacid 4 or ester 3 with an electrophillic agent makes a 6-substituted2H-1-benzopyran 5. A wide variety of electrophillic agents reactselectively with 2H-1-benzopyrans 4 in the 6-position to provide newanalogs in high yield. Electrophillic reagents such as halogen (chlorineor bromine) give the 6-halo derivatives. Chlorosulfonic acid reacts toafford the 6-position sulfonyl chloride that can further be converted toa sulfonamide or sulfone. Friedel-Crafts acylation of 4 provides6-acylated 2H-1-benzopyrans in good to excellent yield. A number ofother electrophiles can be used to selectively react with these2H-1-benzopyrans in a similar manner. A 6-position substituted2H-1-benzopyran can react with an electrophilic reagent at the8-position using similar chemistries to that described for electrophilicsubstitution of the 6-position. This yields an 2H-1-benzopyran which issubstituted at both the 6 and 8 positions.

[0681] Synthetic Scheme 3 illustrates a second general synthesis ofsubstituted 2H-1-benzopyran-3-carboxylic acids which allows substitutionat position 4 of the 2H-1-benzopyran. In this case a commercially orsynthetically available subtituted ortho-hydroxy acetophenone 6 istreated with two or more equivalents of a strong base such as lithiumbis(trimethylsilyl)amide in a solvent such as tetrahydrofuran (THF),followed by reaction with diethyl carbonate to afford the beta-ketoester 7. Ester 7 is condensed with an acid chloride or anhydride in thepresence of a base such as potassium carbonate in a solvent such astoluene with heat to afford 4-oxo-4H-1-benzopyran 8. Reduction of theolefin can be accomplished by a variety of agents including sodiumborohydride (NaBH₄) in solvent mixtures such as ethanol andtetrahydrofuran (THF), or by use of triethylsilane in a solvent such astrifluoroacetic acid, or by catalytic reduction using palladium oncharcoal and hydrogen gas in a solvent such as ethanol to yield the newbeta-keto ester 9 (two tautomeric structures shown). Acylation of theoxygen of the ketone enolate in the presence of a base such as2,6-di-tert-butyl-4-methylpyridine, an acylating agent such astrifluoromethanesulfonic anhydride, and using a solvent such asmethylene chloride yields the enol-triflate 10. Triflate 10 can bereduced with reagents such as tri-n-butyltin hydride, lithium chlorideand a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R″ is hydrogen.The ester 11 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired substituted 2H-1-benzopyran-3-carboxylicacid.

[0682] To incorporate a carbon fragment R³ one can treat triflate 10with reagents known to undergo “cross-coupling” chemistries such atributylethyenyltin, lithium chloride and a palladium(0) catalyst suchas tetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R³ is a vinylmoiety. The ester 6 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired 4-vinyl-2H-1-benzopyran-3-carboxylic acid(12, R″═CH₂CH—). Similarly triflate 10 can be converted under similarconditions using tri-n-butylphenyltin to 2H-1-benzopyran where R³=phenyland by hydrolysis of the ester converted to the carboxylic acid 12 whereR³=phenyl. Using a similar strategy, substituents which be incorporatedas substitutent R³ can be substituted olefins, substituted aromatics,substuted heteroaryl, acetylenes and substituted acetylenes.

[0683] Synthetic Scheme 4 shows an alternative general procedure for thepreparation of 4-oxo-4H-1-benzopyran 8. Treatment of anortho-fluorobenzoyl chloride with an appropriately substituted beta-ketoester 14 with a base such as potassium carbonate in a solvent such astoluene provides 4-oxo-4H-1-benzopyran 8. 4-Oxo-4H-1-benzopyran 8 can beconverted to 2H-1-benzopyran 12 as described in Scheme 3.

[0684] Synthetic Scheme 5 shows a general method for substitution of thearomatic ring of the 2H-1-benzopyran. This can be accomplished throughorgano-palladium mediated “cross-coupling” chemistries using a palladium(0) catalyst to couple benzopyran 15 at position Y, where Y is iodide,bromide or triflate, with an acetylene, olefin, nitrile, or arylcoupling agent. Substituted acetylenes as the coupling agent willprovide the corresponding substituted acetylene. Substituted arylmoieties can be incorporated using arylboronic acids or esters; nitritescan be incorporated by use of zinc (II) cyanide. The resulting ester 16can be converted to carboxylic acid 17 as described in Scheme 1.

[0685] Another approach to substitution of the aryl moiety of thebenzopyran 15 is to convert Y, where Y is iodide or bromide, to aperfluoroalkyl moiety. Exemplary of this transformation is theconversion of 15 (Y=iodide) to 16 (R^(2′)=pentafluoroethyl) using apotassium pentafluoropropionate and copper (I) iodide inhexamethylphosphoramide (HMPA). The resulting ester 16 can be convertedto carboxylic acid 15 as described in Scheme 1.

[0686] A similar method adds substitution of the aromatic ring indihydroquinoline-3-carboxylates. This can be accomplished throughorganopalladium couplings with aryl iodides, bromides, or triflates andvarious coupling agents (R. F. Heck, Palladium Reagents in OrganicSynthesis. Academic Press 1985). When using a suitable palladiumcatalyst such as tetrakis(triphenyl-phospine)palladium(0) in thisreaction, coupling agents such as alkynes provide disubstituted alkynes,phenyl boronic acids afford biphenyl compounds, and cyanides producearylcyano compounds. A number of other palladium catalysts and couplingreagents could be used to selectively react with appropriatelysubstituted dihydroquinoline-3-carboxylates in a similar manner.

[0687] Synthetic Scheme 6 shows a general synthetic route for conversionof a commercially or synthetically available substituted phenol into asubstituted salicylaldehyde. Several different methods which utilizeformaldehyde or a chemically equivalent reagent are described in detailbelow.

[0688] Reaction of an appropriately substituted phenol 18 in basic mediawith formaldehyde (or chemical equivalent) will yield the correspondingsalicylaldehyde 1. The intermediate, ortho-hydroxymethylphenol 19, willunder appropriate reaction conditions be oxidized to the salicylaldehyde1 in situ. The reaction commonly employs ethyl magnesium bromide ormagnesium methoxide(one equivalent) as the base, toluene as the solvent,paraformaldehyde (two or more equivalents) as the source offormaldehyde, and employs hexamethylphoramide (HMPA) orN,N,N′,N′-tetramethylethylenediamine (TMEDA). (See: Casiraghi, G. etal., J. C. S. Perkin I, 1978, 318-321.)

[0689] Alternatively an appropriately substituted phenol 18 may reactwith formaldehyde under aqueous basic conditions to form the substitutedortho-hydroxybenzyl alcohol 19 (See: a) J. Leroy and C. Wakselman, J.Fluorine Chem., 40, 23-32 (1988). b) A. A. Moshfegh, et al., Helv. Chim.Acta., 65, 1229-1232 (1982)). Commonly used bases include aqueouspotassium hydroxide or sodium hydroxide. Formalin (38% formaldehyde inwater) is commonly employed as the source of formaldehyde. The resultingortho-hydroxybenzyl alcohol 19 can be converted to the salicylaldehyde 1by an oxidizing agent such as manganese (IV) dioxide in a solvent suchas methylene chloride or chloroform (See: R-G. Xie, et al., SyntheticCommun. 24, 53-58 (1994)).

[0690] An appropriately substituted phenol 18 can be treated underacidic conditions with hexamethylenetetramine (HMTA) to prepare thesalicylaldehyde 1 (Duff Reaction; See: Y. Suzuki, and H. Takahashi,Chem. Pharm. Bull., 31, 1751-1753 (1983)). This reaction commonlyemploys acids such as acetic acid, boric acid, methanesulfonic acid, ortrifluoromethanesulfonic acid. The source of formaldehyde commonly usedis hexamethylenetetramine.

[0691] Synthetic Scheme 7 shows the Reimer-Tiemann reaction in which ancommercially or synthetically available appropriately substituted phenol18 will under basic conditions react with chloroform to yield asubstituted salicylaldehyde 1 (See: Cragoe, E. J.; Schultz, E. M., U.S.Pat. No. 3,794,734, 1974).

[0692] Synthetic Scheme 8 shows the conversion of a commercially orsynthetically available appropriately substituted salicylic acid 21 toits respective salicylaldehyde 1 via an intermediate 2-hydroxybenzylalcohol 19. Reduction of the salicylic acid 21 can be accomplished witha hydride reducing agent such as borane in a solvent such astetrahydrofuran. Treatment of the intermediate 2-hydroxybenzyl alcohol19 with an oxidizing agent such as manganese (IV) oxide in a solventsuch as methylene chloride or chloroform provides salicylaldehyde 1.

[0693] Synthetic Scheme 9 illustrates a general synthetic method forpreparation of a wide variety of substituted2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acids (25). In step1, an appropriately commercially or synthetically available substitutedthiophenol 22 is ortho-metallated with a base such as n-butyllithiumemploying TMEDA (N,N,N′,N′-tetramethylethylenediamine) followed bytreatment with dimethylformamide to provide the 2-mercaptobenzaldehyde23. Condensation of the 2-mercaptobenzaldehyde 23 with an acrylate 2 inthe presence of base provides ester 24 which can be saponified in thepresence of aqueous base to afford the substituted2H-1-benzothiopyran-3-carboxylic acids 25.

[0694] Synthetic Scheme 10 shows a method for preparing a substituted2-mercaptobenzaldehyde from an appropriate commercially or syntheticallyavailable substituted salicylaldehyde. In step 1, the phenolic hydroxylof salicylaldehyde 1 is converted to the corresponding O-arylthiocarbamate 26 by acylation with an appropriately substitutedthiocarbamoyl chloride such as N,N-dimethylthiocarbamoyl chloride in asolvent such as dimethylformamide using a base such as triethylamine. InStep 2, O-aryl thiocarbamate 26 rearranges to S-aryl thiocarbamate 27when heated sufficiently such as to 200° C. using either no solvent or asolvent such as N,N-dimethylaniline (See: A. Levai, and P. Sebok, Synth.Commun., 22 1735-1750 (1992)). Hydrolysis of S-aryl thiocarbamate 27with a base such as 2.5 N sodium hydroxide in a solvent mixture such astetrahydrofuran and ethanol yields the substituted2-mercaptobenzaldehyde 23 which can be converted to the substituted2H-1-benzothiopyran-3-carboxylic acids 25 as described in Scheme 9.

[0695] Synthetic Scheme 11 illustrates the general method for thepreparation of a wide variety of dihydroquinoline-3-carboxylic acidderivatives 30. R² represents the aromatic substitution of commerciallyand synthetically available 2-aminobenzaldeydes 28. The2-amino-benzaldehyde derivative 28, where R² represents varioussubstitutions, is condensed with a acrylate derivative 2 in the presenceof base such as potassium carbonate, triethylamine, ordiazbicyclo[2.2.2]undec-7-ene in solvents such as dimethylformamide toafford the dihydroquinoline-3-carboxylate esters 29. The ester 29 can besaponified to the corresponding acid, such as by treatment with aqueousinorganic base such as 2.5 N sodium hydroxide in a suitable solvent suchas ethanol to afford after acidification the desireddihydroquinoline-3-carboxylic acid 30.

[0696] Synthetic Scheme 12 illustrates the preparation ofdihydroquinoline-3-carboxylic acid 30 from 2-aminobenzoic acids 31. R²represents the aromatic substitution of commercially and syntheticallyavailable 2-aminobenzoic acids 31. Reduction of the representative2-aminobenzoic acid 31 to the desired 2-aminobenzyl alcohol 32 wasaccomplished with a hydride reducing agent such as borane in a solventsuch as tetrahydrofuran. Treatment of the desired 2-aminobenzyl alcohol32 with an oxidizing agent such as manganese(IV)oxide in a solvent suchas methylene chloride provides the representative 2-aminobenzaldehydes28. (C. T. Alabaster, et al. J. Med. Chem. 31, 2048-2056 (1988)) The2-aminobenzaldehydes were converted to the desireddihydroquinoline-3-carboxylic acid 30 as described in Scheme 11.

[0697] Synthetic Scheme 13 illustrates the general method for thepreparation of a wide variety of dihydroquinoline-3-carboxylic acidderivatives 30 from isatins 33. R² represents the aromatic substitutionof commercially and synthetically available isatins 33. A representativeisatin 33 was treated with basic peroxide generated from hydrogenperoxide and a base such as sodium hydroxide to afford the desiredrepresentative 2-aminobenzoic acids 31. (M. S. Newman and M. W. Lougue,J. Org. Chem., 36, 1398-1401 (1971)) The 2-aminobenzoic acids 31 aresubsequently converted to the desired dihydroquinoline-3-carboxylic acidderivatives 30 as described in synthetic Scheme 12.

[0698] Synthetic Scheme 14 is another general method for the preparationof dihydroquinoline-3-carboxylic acid derivatives 30. In step 1, anappropriate commercially or synthetically available substituted aniline34 can be treated with an acylating reagent such as pivaloyl chlorideyielding an amide 35. The ortho-dianion of amide 35 is prepared bytreating amide 35 with organo-lithium bases such as n-butyllithium ortert-butyllithium in tetrahydrofuran at low temperature. The dianion isquenched with dimethylformamide to afford theacylated-2-amino-benzaldehydes 36. (J. Turner, J. Org. Chem., 48,3401-3408 (1983)) Reaction of these aldehydes in the presence of basessuch as lithium hydride with a acrylate followed by work up with aqueousinorganic bases and hydrolysis, such as by treatment with aqueous base(sodium hydroxide) in a suitable solvent such as ethanol affords, afteracidification, a dihydroquinoline-3-carboxylic acid 30.

[0699] Synthetic Scheme 15 shows a general method for alkylation of thenitrogen of dihydroquinoline-3-carboxylate ester derivatives 29. Thestep involves treatment of dihydroquinoline-3-carboxylate esterderivatives 29 with alkyl halides such as iodoethane in the presence ofphase transfer catalysts such a tetrabutylammonium iodide, and a basesuch as caustic (50% aqueous sodium hydroxide) in a solvent such asdichloromethane. These conditions afford the N-alkylateddihyrdoquinoline-3-carboxylate esters 37. Saponification of 37 withaqueous base provides N-alkylated-dihyroquinoline-3-carboxylic acidderivatives 38.

[0700] Synthetic Scheme 16 shows a general method for the preparation ofa 7-ether (Z¹=O) or thioether ¹=S) substituted benzopyran-3-carboxylicester. An appropriately substituted phenol, thiophenol,hydroxy-heterocycle, mercaptoheterocycle, alcohol, or alkylthiol can becondensed under basic conditions using a base such as potassiu carbonatein a solvent such as di ethysulfoxide at te perature above roo teperature such as 100° C., with an appropriately substituted7-fluorobenzopyran derivative 30 to yield the corresponding ether orthioether. ydrolysis of the ester with an aqueous base such as lithiuhydroxide or sodiu hydroxide in a solvent ixture such astetrahydrofuran-ethanol-water yields acid hen appropriate a thioether²=S) can be oxidi ed to the sulfoxide ²=SO) or sulfone (Z²=SO₂) with anoxidant such as OXONE® or m-CPBA either before or after esterhydrolysis. In this chemistry R^(d) can include aryl, heteroaryl,heterocyclic, alicyclic, branched or linear aliphatic branched or linearperfluoro-aliphatic oiety.

[0701] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-II. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

[0702] The following abbreviations are used:

[0703] HCl—hydrochloric acid

[0704] MgSO₄—magnesium sulfate

[0705] Na₂SO₄—sodium sulfate

[0706] DMF—dimethylformamide

[0707] THF—tetrahydrofuran

[0708] NaOH—sodium hydroxide

[0709] EtOH—ethanol

[0710] K₂CO₃—potassium carbonate

[0711] CDCl₃—deuterated chloroform

[0712] CD₃OD—deuterated methanol

[0713] Et₂O—diethyl ether

[0714] EtOAc—ethyl acetate

[0715] NaHCO₃—sodium bicarbonate

[0716] KHSO₄—potassium sulfate

[0717] NaBH₄—sodium borohydride

[0718] TMEDA—tetrametylethylenediamine

[0719] HMTA—hexamethylenetetraamine

[0720] DMSO—dimethyl sulfoxide

[0721] HMPA hexamethyl phosphoric triamide

[0722] h—hour

[0723] P₂O₅—phosphorous pentoxide

[0724] HOAc—acetic acid

[0725] NaOD—deuterated sodium hydroxide

[0726] n-BuLi—n-butyllithium

[0727] CH₂Cl₂—methylene chloride

[0728] TFA—trifluoroacetic acid

[0729] OXONE—potassium peroxymonosulfate

EXAMPLE 1

[0730]

[0731] 6-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0732] Step 1. Preparation of ethyl6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

[0733] A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) andethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved inanhydrous DMF, warmed to 60° C. and treated with anhydrous K₂CO₃ (17.75g, 0.128 mole). The solution was maintained at 60° C. for 20 hours,cooled to room temperature, and diluted with water. The solution wasextracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo toafford 54.32 g of an oil. The oil was dissolved in 250 mL of methanoland 100 mL of water, whereupon a white solid formed that was isolated byfiltration, washed with water and dried in vacuo, to afford the ester asa yellow solid (24.31 g, 62%): mp 62-64° C. ¹H NMR (CDCl₃/90 MHz) 7.64(s, 1H), 7.30−7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30(q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).

[0734] Step 2. Preparation of6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[0735] A solution of the ester from Step 1 (13.02 g, 42 mmole) wasdissolved in 200 mL of methanol and 20 mL of water, treated with lithiumhydroxide (5.36 g, 0.128 mole) and stirred at room temperature for 16hours. The reaction mixture was acidified with 1.2 N HCl, whereupon asolid formed that was isolated by filtration. The solid was washed with200 mL of water and 200 mL of hexanes and dried in vacuo to afford thetitle compound as a yellow solid (10.00 g, 85%): mp 181-184° C.

EXAMPLE 2

[0736]

[0737] 6-(Methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0738] Step 1. Preparation of 5-(methylthio)salicylaldehyde.

[0739] Ethyl magnesium bromide (38 mL of a 3.0 M solution in diethylether, 113.8 mmole) was chilled with an ice-water bath. To the chilledsolution was added a solution of 4-(methylthio)phenol (15.95 g, 113.8mmole) in diethyl ether (30 mL) over 0.15 hour during which time gas wasevolved. The reaction was held at 0° C. for 0.5 hour, at roomtemperature for 0.5 hour, and the addition funnel replaced with adistillation head. Toluene (250 mL) and the diethyl ether were distilledout of the reactor. The reaction was cooled, toluene (250 mL) andhexamethylphosphoramide (HMPA) (19.8 mL, 20.4 g, 113.8 mmole) wereadded, and the resulting mixture was stirred for 0.25 hours. Thedistillation head was replaced with a condenser and paraformaldehyde(8.5 g, 284.4 mmole) was added. The reaction was heated to 90° C. for 3hours. The reaction mixture was cooled to room temperature, wasacidified with 1N HCl and the layers separated. The organic phase waswashed with water, and with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to yield a solid. This solid was purified bysilica chromatography (hexanes-ethyl acetate, 5:1) yielding thesalicylaldehyde as a yellow crystalline solid (6.01 g) of suitablepurity to be used in the next reaction without further purification.

[0740] Step 2. Preparation of ethyl6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[0741] 5-Methylthiosalicylaldehyde (Step 1)(2.516 g, 14.96 mmole) wasadded to dimethylformamide (3.5 mL), potassium carbonate (2.27 g, 16.45mmole) and ethyl 4,4,4-trifluorocrotonate (3.3 mL, 3.8 g, 22.4 mmole).The mixture was heated to 65° C. for 3 h. The reaction was cooled toroom temperature, poured into H₂O (50 mL), and extracted with diethylether (2×75 mL). The combined ethereal phases were washed with aqueousNaHCO₃ solution (3×50 mL), aqueous 2 N HCl solution (3×50 mL), and brine(3×50 mL), dried over MgSO₄, filtered, diluted with isooctane andpartially concentrated in vacuo causing the precipitation of the ethylester (2.863 g, 60%) as a yellow powder: mp 87.8-89.6° C. This ester wasof suitable purity to use without further purification.

[0742] Step 3. Preparation of6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[0743] The ester (Step 2) was hydrolyzed to form the carboxylic acid viaa method similar to that described in Example 1, Step 2: mp 166.3-167.9°C. ¹H NMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.43 (d, 1H, J=2.2 Hz),7.33 (dd, 1H, J=8.5, 2.4 Hz), 6.98 (d, 1H, J=8.5 Hz), 5.79 (q, 1H, J=7.0Hz), 2.48 (s, 3H). FABLRMS m/z 291 (M+H). ESHRMS m/z 289.0152 (M−H,Calc'd 289.0146). Anal. Calc'd for C₁₂H₉F₃O₃S₁: C, 49.66; H, 3.13; S,11.05. Found: C, 49.57; H, 3.02; S, 11.37.

EXAMPLE 3

[0744]

[0745] 7-Methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0746] 3-Methylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 202.1-203.1° C. ¹H NMR(CDCl₃/300 MHz) 7.84 (s, 1H), 7.12 (d, 1H, J=8.3 Hz), 6.82 (m, 2H), 5.65(q, 1H, J=6.8 Hz), 2.35 (s, 3H). FABLRMS m/z 259 (M+H). FABHRMS m/z259.0576 (M+H, Calc'd 259.0582). Anal. Calc'd for C₁₂H₉F₃O₃: C, 55.82;H, 3.51. Found: C, 55.93; H, 3.59.

EXAMPLE 4

[0747]

[0748] 2,7-bis(Trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[0749] 3-(Trifluoromethyl)phenol was converted to the title compound bya procedure similar to that described in Example 2: mp 190.3-193.5° C.¹H NMR (acetone-d₆/300 MHz) 7.98 (s, 1H), 7.73 (d, 1H, J=7.9 Hz), 7.46(d, 1H, J=7.9 Hz), 7.36 (s, 1H), 5.93 (q, 1H, J=7.1 Hz) FABLRMS m/z 313(M+H). FABHRMS m/z 313.0267 (M+H, Calc'd 313.0299). Anal. Calc'd forC₁₂H₆F₆O₃: C, 46.17; H, 1.94. Found: C, 46.25; H, 2.00.

EXAMPLE 5

[0750]

[0751] 7-Bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0752] 3-Bromophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 198.4-199.5° C. ¹H NMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.43 (d, 1H, J=8.1 Hz), 7.31 (s, 1H),7.30 (d, 1H, J=8.1 Hz), 5.84 (q, 1H, J=7.1 Hz). FABLRMS m/z 323 (M+H).Anal. Calc'd for C₁₁H₆BrF₃O₃: C, 40.90; H, 1.87. Found: C, 41.00; H,1.85.

EXAMPLE 6

[0753]

[0754] 6-Chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0755] 4-Chloro-3-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 207.5-209.3° C. ¹HNMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 5.65 (q,1H, J=6.8 Hz), 2.37 (s, 3H). FABLRMS m/z 292 (M+H). FABHRMS m/z 299.0287(M+Li, Calc'd 299.0274). Anal. Calc'd for C₁₂H₈ClF₃O₃: C, 49.25; H,2.76; Cl, 12.11. Found: C, 49.37; H, 2.82; Cl, 12.17.

EXAMPLE 7

[0756]

[0757]6-(4-Methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0758] 4-(4-Methoxyphenyl)phenol was converted to the title compound bya procedure similar to that described in Example 2: mp 181.7-182.9° C.¹H NMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.11 (m, 1H), 7.02 (m, 2H),6.98 (m, 4H), 5.81 (q, 1H, J=7.0 Hz), 3.80 (s, 3H). FABLRMS m/z 365(M−H). FABHRMS m/z 367.0809 (M+H, Calc'd 367.0793). Anal. Calc'd forC₁₈H₁₃F₃O₅: C, 59.02; H, 3.58. Found: C, 59.10; H, 3.61.

EXAMPLE 8

[0759]

[0760]6-Chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0761] Step 1. Preparation of 4-tert-butylsalicylaldehyde

[0762] A five liter three-neck round bottom flask equipped with overheadmechanical stirrer and condenser was charged with trifluoroacetic acid(2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424g, 3.0 mole) was added portion-wise causing an exotherm. With cooling,the temperature was maintained under 80° C. The reaction was heated at80° C. for one hour, then cooled, and water (2 L) added. After 0.5 houradditional water (4 L) was added and the mixture was extracted withethyl acetate (6 L). The organic extract was washed with water andbrine. The resulting organic phase was divided into 2 L volumes and eachdiluted with water (1 L), and solid NaHCO₃ added until the mixture wasneutralized. The organic phases were isolated and combined, dried overMgSO₄, filtered and concentrated in vacuo yielding an oil. This oil wasdistilled at 95° C. (0.8 mm) yielding the desired salicylaldehyde as anoil (272.9 g, 56%) which was of sufficient purity to be used withoutfurther purification.

[0763] Step 2. Preparation of ethyl7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

[0764] A one liter three-neck flask was charged with4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mole),dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole)causing the temperature of the mixture to rise to 40° C. Ethyl4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110mL) was added and the mixture heated to 60° C. at which time thereaction temperature rose to 70° C. The reaction was cooled to 60° C.,maintained at 60° C. (with added heating) for 8.5 hours and cooled toroom temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) wereadded, mixed, and the layers separated. The aqueous phase was extractedwith ethyl acetate and the organic phases were combined. The combinedorganic phases were washed with brine-water (1:1), brine, dried overMgSO₄, filtered and concentrated in vacuo, yielding a semi-solid. Hexane(600 mL) was added with mixing and the mixture was filtered. Thefiltrate was washed with brine, dried over MgSO₄, filtered andconcentrated in vacua yielding a solid. This solid was dissolved in hotethanol (600 mL). Water (190 mL) was added which inducedcrystallization. Filtration of the mixture and drying of the productprovided the desired ester as a crystalline solid (131.3 g, 71%): mp91.0-94.9° C. This material was of suitable purity to be used insubsequent steps without further purification.

[0765] Step 3. Preparation of ethyl6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

[0766] A one liter three-neck flask equipped with mechanical stirrer andgas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) andacetic acid (300 mL). While cooling (water bath) the reaction mixture,chlorine gas (37.6 g, 0.53 mole) was added which caused the temperatureto rise to 48° C. After stirring for two hours, the reaction was cooledin an ice-water bath to 15° C. Zinc powder (19.5 g, 0.3 mole) was addedin one portion which caused the temperature to rise to 72° C. Aftercooling to room temperature additional zinc powder (5.0 g, 0.08 mole)was added and the mixture was stirred for 0.5 hour longer. The crudemixture was filtered through diatomaceous earth and was concentrated invacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL)washed with brine-water (1:1, 1 L) and brine (0.5 L). The resultingaqueous phase was extracted with ethyl acetate (700 mL). This ethylacetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L).The combined organic phases were dried over MgSO₄, filtered andconcentrated in vacuo yielding the title compound as a yellow oil (116g, 106%). This material, which contained some entrained ethyl acetate,was of suitable purity to be used in subsequent steps without furtherpurification.

[0767] Step 4. Preparation of6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0768] To a solution of the ester (Step 3) (116 g, 0.3 mole) in methanol(500 mL) and tetrahydrofuran (500 mL) in a one liter flask was addedaqueous sodium hydroxide (2.5 N, 240 mL, 0.6 mole). After stirringovernight, the pH of the solution was adjusted to 1 with concentratedhydrochloric acid and the solution was extracted with ethyl acetate. Theethyl acetate phase was dried over MgSO₄, filtered and concentrated invacuo yielding a solid. This solid was dissolved in hot ethanol (500mL). Water (500 mL) was added and upon cooling to room temperaturecrystals formed which were collected by vacuum filtration. The crystalswere washed with ethanol-water (3:7, 3×200 mL) and dried providing thetitle acid as a crystalline solid (91.6 g, 91%): mp 194.9-196.5° C. ¹HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83(q, 1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C₁₅H₁₄ClF₃O₃: C,53.83; H, 4.22; Cl, 10.59. Found: C, 53.92; H, 4.24; Cl, 10.50.

EXAMPLE 9

[0769]

[0770]6-(3-Chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0771] To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24M solution, 0.84 mmol) was added6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorinein acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. Afterthree additional hours additional chlorine in acetic acid (0.25 ml of0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction wasquenched with aqueous 10% sodium bisulfite solution and the resultingmixture extracted with ethyl acetate. The organic phase was washed withwater, brine, dried over MgSO₄, filtered, and concentrated in vacuoyielding a brown oil. The oil was dissolved in a minimum of hexaneswhich induced crystallization. Vacuum filtration of the mixture providedthe title compound as yellow crystals (0.18 g, 53%): mp 205-207° C. ¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H,J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249(M−H, Calc'd 399.0247). Anal. Calc'd for C₁₈H₁₂ClF₃O₅: C, 53.95; H,3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.

EXAMPLE 10

[0772]

[0773] 2-Trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0774] Step 1. Preparation of ethyl2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[0775] The ester was prepared from salicylaldehyde by a proceduresimilar to the method described in Example 1, Step 1: bp 107° C. 2mm.¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.52−7.38 (m, 2H), 7.09 (dt, 1J=1.0, 7.7 Hz), 7.03 (d, 1H, J=8.3 Hz), 5.84 (q, 1H, J=7.3 Hz),4.39−4.23 (m, 2H), 1.33 (t, 3H, J=7.0 Hz). FABLRMS m/z 273 (M+H). ESHRMS(m/z 273.0720 (M+H Calcd 273.0739)

[0776] Step 2. Preparation of2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[0777] The acid was prepared from the ethyl ester (Step 1) by aprocedure similar to the method described in Example 1, Step 2: mp152.2-153.3° C. ¹H NMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.39-7.49 (m,2H), 7.11−7.01 (m, 2H), 5.81 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z245.0422 (M+H, Calc'd 245.0426). Anal. Calc'd for C₁₁H₇F₃O₃: C, 54.11;H, 2.89. Found: C, 54.22; H, 2.97.

EXAMPLE 11

[0778]

[0779]6,8-Dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[0780] Step 1. Preparation of 3,5-dichloro-4-methylsalicylaldehyde

[0781] 2,4-Dichloro-3-methylphenol (25.0 g, 141.2 mmol) was added tomethanesulfonic acid (100 mL). With stirring, hexamethylenetetramine(HMTA) (39.8g, 282.4 mmol) and additional methanesulfonic acid (100 mL)was added portion-wise during which time the reaction began to froth andexotherm. The resulting mixture was heated to 100° C. for 3 hours. Thecrude ocher colored suspension was cooled to 50° C. and poured over amechanically stirred mixture of ice-water (2 L). A yellow precipitatewas formed which was collected by vacuum filtration. This solid waspurified by flash chromatography (silica, hexanes-methylene chloride,9:10) yielding the salicylaldehyde as a pale yellow powder (6.17 g, 21%;mp 94.0-95.1° C.) of suitable purity to use without furtherpurification.

[0782] Step 2. Preparation of ethyl6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

[0783] A mixture of 3,5-dichloro-4-methylsalicylaldehyde (Step 1)(5.94g, 29.0 mmol) and ethyl 4,4,4-trifluorocrotonate (7.67 g, 45.6 mmol)dissolved in anhydrous DMSO (10 mL) was treated with triethylamine (5.88g, 58.1 mmol). The reaction was stirred at 85° C. for 49 hours thencooled in ice and filtered to give an orange solid. The solid wasdissolved in ethyl acetate (100 mL), washed with 3 N HCl (2×50 mL),saturated NaHCO₃, washed with brine, dried over MgSO₄, and concentratedin vacuo to give a yellow solid (8.63 g, 84%): mp 117.1-119.5° C. ¹H NMR(CDCl₃/300 MHz) 7.63 (s, 1H), 7.17 (s, 1H), 5.80 (q, 1H, J=6.6 Hz), 4.33(m, 2H), 2.48 (s, 3H), 1.35 (t, 3H, J=7.1 Hz). Step 3. Preparation of6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[0784] The ester from Step 2 (8.39 g 23.6 mmol) was dissolved in THF (30mL) and ethanol (20 mL), treated with 2.5 N sodium hydroxide (20 mL, 50mmol), and stirred at room temperature for 3.5 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl, filtered, andrecrystallized from ethanol/water to yield a yellow solid (6.0 g, 78%):mp 229.9-230.9° C.

[0785]¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.58 (s, 1H), 6.00 (q,1H, J=6.8 Hz), 2.50 (s, 3H). FABLRMS m/z 325 (M−H). FABHRMS m/z 324.9636(M−H, Calc'd 324.9646). Anal. Calc'd for C₁₂H₇Cl₂F₃O₃: C, 44.07; H,2.16; Cl, 21.68. Found: C, 44.06; H, 2.21; Cl, 21.74.

EXAMPLE 12

[0786]

[0787]7-(1,1-Dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0788] Ethyl7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 8, Step 2) was hydrolyzed to the carboxylic acid via aprocedure similar to that described in Example 1, Step 2: mp165.6-166.8° C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.38 (d, 1H,J=8.1 Hz), 7.15 (dd, 1H, J=1.8 Hz, and J=7.8 Hz), 7.05 (bs, 1H), 5.79(q_(H−F), 1H, J=7.2 Hz), 1.32 (s, 9H). FABHRMS m/z 301.1033 (M+H, Calc'd301.1051). Anal. Calc'd for Cl₁₅H₁₅F₃O₃: C, 60.00; H, 5.04. Found: C,59.80; H, 5.10.

EXAMPLE 13

[0789]

[0790] 6-Bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0791] 5-Bromosalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 189.6-190.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.70 (d, 1H, J=2.1 Hz), 7.55 (dd,1H, J=2.4 Hz, and J=8.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 5.86 (q _(H−F), 1H,J=7.2 Hz). FABHRMS m/z 322.9519 (M+H, Calc'd 322.9531). Anal. Calc'd forC₁₁H₆BrF₃O₃: C, 40.90; H, 1.87; Br, 24.73. Found: C, 40.87; H, 1.92; Br,24.80.

EXAMPLE 14

[0792]

[0793] 8-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0794] 2-Chlorophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 224.5-225.6° C. ¹H NMR(acetone-d₆/300 MHz) 7.91 (s, 1H), 7.49 (m, 2H), 7.11 (t, 1H, J=7.8 Hz),5.96 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 279.0027 (M+H, Calc'd279.0036). Anal. Calc'd for C₁₁H₆ClF₃O₃: C, 47.42; H, 2.17. Found: C,47.33; H, 2.17.

EXAMPLE 15

[0795]

[0796] 8-Bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0797] 2-Bromo-4-chlorosalicylaldehyde was converted to the titlecompound by a similar procedure to that described in Example 1: mp227.8-228.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H,J=2.4 and J=28.8 Hz), 6.00 (q_(H=F), 1H, J=7.2 Hz). FABHRMS m/z 356.9134(M+H, Calc'd 356.9141). Anal. Calc'd for C₁₁H₅BrClF₃O₃: C, 36.96; H,1.41. Found: C, 37.05; H, 1.33.

EXAMPLE 16

[0798]

[0799] 6-Trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0800] 5-(Trifluoromethoxy)salicylaldehyde was converted to the titlecompound by a similar procedure to that described in Example 1: mp118.4-119.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.95 (s, 1H), 7.54 (d, 1H,J=2.1 Hz), 7.39 (dd, 1H, J=2.4 Hz, and J=9.0 Hz), 7.02 (d, 1H, J=9.0Hz), 5.88 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 329.0228 (M+H, Calc'd329.0249). Anal. Calc'd for C₁₂H₆F₆O₄: C, 43.92; H, 1.84. Found: C,43.84; H, 1.87.

EXAMPLE 17

[0801]

[0802] 8-Fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0803] 3-Fluorosalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 1: mp 197.7-210.1° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.30 (m, 2H), 7.11 (m 1H), 5.93(q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 263.0341 (M+H, C₁₁H₆F₄O₃ Calc'd263.0331). Anal. Calc'd for C₁₁H₆F₄O₃: C, 50.40; H, 2.31. Found: C,50.48; H, 2.25.

EXAMPLE 18

[0804]

[0805] 5,7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0806] 4,6-Dichlorosalicylaldehyde was converted to the title compoundby a similar procedure to that described in Example 1: mp 190.1-191.2°C. ¹H NMR (acetone-d₆/300 MHz) 8.01 (s, 1H), 7.3 (bs, 1H), 7.16 (bs,1H), 5.94 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 312.9636 (M+H, Calc'd312.9646). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20; H, 1.61. Found: C,42.27; H, 1.56.

EXAMPLE 19

[0807]

[0808] 7,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0809] 3,4-Dichlorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 219.5-220.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d,1H, J=8.4 Hz), 6.02 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 318.9709 (M+Li,C₁₁H₅Cl₂F₃O₃ Calc'd 318.9728). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20;H, 1.61. Found: C, 42.15; H, 1.68.

EXAMPLE 20

[0810]

[0811] 7-Isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0812] 2,4-Dihydroxybenzaldehyde was alkylated to prepare4-(1-methylethyloxy)salicylaldehyde. This salicylaldehyde was convertedto the title compound by a similar procedure to that described inExample 1: mp 161-163° C. ¹H NMR (CD₃OD/300 MHz) 7.73 (s, 1H), 7.21 (d,1H, J=8.5 Hz), 6.57 (dd, 1H, J=8.5, 2.2 Hz). FABHRMS m/z 301.0688 (M−H⁺,C₁₁H₁₂F₃O₄ requires 301.0687). Anal. Calc'd for C₁₁H₁₃F₃O₄: C, 55.63; H,4.34. Found: C, 55.72; H, 4.34.

EXAMPLE 21

[0813]

[0814] 8-Phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0815] 2-Phenylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 171.6-175.0° C. ¹H NMR(acetone-d₆/300 MHz) 7.95 (s, 1H), 7.46 (m, 7H), 7.18 (t, 1H, J=7.5 Hz),5.81 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 327.0816 (M+Li, Calc'd327.0820). Anal. Calc'd for C₁₇H₁₁F₃O₃: C, 63.76; H, 3.46. Found: C,63.52; H, 3.55.

EXAMPLE 22

[0816]

[0817] 7,8-Dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0818] 2,3-Dimethylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 245.2-247.3° C. ¹HNMR (acetone-d₆/300MHz) 7.83 (s, 1H), 7.17 (d, 1H, J=7.8 Hz), 6.89 (d,1H, J=7.8 Hz), 5.82 (q_(H−F), 1H, J=7.2 Hz), 2.30 (s, 3H), 2.17 (s, 3H).Anal. Calc'd for C₁₃H₁₁F₃O₃+1.56% H₂O: C, 56.46; H, 4.18. Found: C,56.46; H, 4.15.

EXAMPLE 23

[0819]

[0820]6,8-bis(1,1-Dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0821] 3,5-Di-tert-butylsalicylaldehyde was converted to the titlecompound by a similar procedure to that described in Example 1: mp171.6-175.0° C. ¹H NMR (acetone-d₆/300 MHz) 7.65 (s, 1H), 7.34 (d, 1H,J=2.4 Hz), 7.15 (d, 1H, J=2.4 Hz), 6.02 (q_(H−F), 1H, J=7.2 Hz). FABHRMSm/z 363.1743 (M+Li, Calc'd 363.1759). Anal. Calc'd for C₁₉H₂₃BrF₃O₃: C,64.03; H, 6.50. Found: C, 64.13; H, 6.49.

EXAMPLE 24

[0822]

[0823] 6-Iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0824] Step 1: Preparation of 2-hydroxy-5-iodobenzyl alcohol

[0825] A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) intetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing,borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) wasadded drop-wise over 0.25 hours. The solution was warmed to roomtemperature and then heated at reflux for 4 h. A white precipitateformed during the reflux. The solution was cooled to room temperatureand 10% aqueous hydrochloric acid (100 mL) was added over 15 min and thesolution stirred at room temperature for 2 h. The precipitate dissolvedand the solvent was concentrated in vacuo to a volume of approximately200 mL. The solution was poured into ethyl acetate (300 mL) and washedwith water (2×200 mL), saturated sodium bicarbonate (2×200 mL), andsaturated ammonium chloride (2×200 mL). The organic layer was dried oversodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzylalcohol was isolated as a white solid (21.3 g, 85.2 mmol)fromhexanes.(90% yield): mp 105-110° C. ¹H NMR (CDCl₃/300 MHz) 8.21 (s, 1H),7.30-7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H).EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).

[0826] Step 2: Preparation of 2-hydroxy-5-iodobenzaldehyde

[0827] To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g,174.0 mmol) in acetone (700 mL) was added 85% activated manganese(IV)oxide (5 micron, 50 g, 494.0 mmol) and the solution stirred at roomtemperature for 16 hours. The manganese oxide was removed by filtrationthrough diatomaceous earth and the filtrate concentrated in vacuo. Theproduct was purified by flash silica chromatography (0-20% ethyl acetatein hexanes) The 2-hydroxy-5-iodobenzaldehyde was obtained as agreenish-yellow solid (24.3 g, 58%). A small amount of the2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol/water toafford an analytical sample and the remainder of the compound was usedwithout further purification: mp 99-101° C. ¹H NMR (CDCl₃/300 MHz) 9.83(s, 1H), 7.79 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=8.7 Hz, J=2.2 Hz), 6.81(d, 1H, J=8.7 Hz). ESHRMS 246.9229 (M−H Calc'd 246.9256).

[0828] Step 3: Preparation of ethyl6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

[0829] A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml,395 mmol)were combined, stirred at 70° C. for 8 h and then heated atreflux for 48 h. The solution was poured into ethyl acetate (300 mL) andwashed with 1N hydrochloric acid (3×200 mL). The aqueous layers werecombined and extracted with ethyl acetate (1×100 mL). The combined ethylacetate extracts were washed with saturated ammonium chloride (2×200mL), dried over magnesium sulfate and concentrated in vacuo yielding adark red oil. This oil was purified by flash chromatography using ethylacetate-hexanes (3:7) yielding a red oil. Crystallization of this oilfrom hexanes yielded the title compound as light red crystals (8.3 g,31%): mp 105-106° C. ¹H NMR (CDCl₃/300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H,J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70(q, 1H, J=6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS415.9926 (M+NH4⁺ Calc'd 396.9746)

[0830] Step 4: Prepartation of6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[0831] Hydrolysis of the ester (Step 3), using a procedure similar toExample 1, Step 2, yielded the carboxylic acid:

[0832] mp 168-170° C. ¹H NMR (CD₃OD/300 MHz) 7.57 (s, 1H), 7.70 (d, 1H,J=2.2 Hz), 7.64 (dd, 1H, J=8.5, 2.2 Hz), 6.79 (d, 1H, J=8.5 Hz) 5.78 (q,1H, J=7.0 Hz). ESHRMS m/z 368.9222 (Calc'd for M−H 368.9235). Anal.Calc'd for C₁₁H₆F₃IO₃: C, 35.70; H, 1.63. Found C, 35.67; H, 1.63.

EXAMPLE 25

[0833]

[0834] 7-(1-Methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0835] 3-(1-Methylethyl)phenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 158.3-159.7° C. ¹HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.37 (d, 1H, J=7.8 Hz), 7.00 (d,1H, J=7.8 Hz), 6.91 (s, 1H), 5.78 (q, 1H, J=6.9 Hz), 2.93 (m, 1H), 1.24(d, 6H, J=6.9 Hz). FABLRMS m/z 287 (M+H). Anal. Calc'd for C₁₄H₁₃F₃O₃:C, 58.74; H, 4.58. Found: C, 57.37; H, 4.49.

EXAMPLE 26

[0836]

[0837] 7-Phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0838] 3-Phenylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 209.4-211.7° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.74 (m, 2H), 7.47 (m, 5H), 7.33 (s,1H), 5.86 (q, 1H, J=7.2 Hz). FABLRMS m/z 321 (M+H). Anal. Calc'd forC₁₇H₁₁F₃O₃: C, 63.76; H, 3.46. Found: C, 64.17; H, 3.61.

EXAMPLE 27

[0839]

[0840] 6-Chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0841] 4-Chloro-3-ethylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 170.7-172.1° C. ¹HNMR (CDCl₃/300 MHz) 7.78 (s, 1H), 7.26 (s, 1H), 6.90 (s, 1H), 5.67 (q,1H, J=6.9 Hz), 2.73 (q, 2H, J=7.8 Hz), 1.24 (t, 3H, J=7.8 Hz). FABLRMSm/z 307 (M+H). Anal. Calc'd for C₁₃H₁₀F₃O₃: C, 50.92; H, 3.29. Found: C,51.00; H, 3.33.

EXAMPLE 28

[0842]

[0843] 8-Ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0844] 2-Ethylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 185.4-186.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.85 (s, 1H), 7.28 (d, 2H, J=7.5 Hz), 7.00 (t, 1H,J=7.5 Hz), 5.84 (q, 1H, J=7.2 Hz), 2.65 (m, 2H), 1.18 (t, 3H, J=7.5 Hz).FABLRMS m/z 273 (M+H). Anal. Calc'd for C₁₃H₁₁F₃O₃: C, 57.36; H, 4.07.Found: C, 57.15; H, 4.11.

EXAMPLE 29

[0845]

[0846] 6-Chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0847] 8-Ethyl-2-(trifluoromethyl)2H-1-benzopyran-3-carboxylic acid(Example 28) (0.68 g, 2.5 mmol) was dissolved in trimethylphosphate (5mL) and was treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0° C.After stirring at 0° C. for 45 minutes and 1 hour at room temperature,the reaction was diluted with cold water (15 mL). The resulting oilymixture was extracted with hexanes-ethyl acetate. The organic phase waswashed with brine, dried, and concentrated in vacuo yielding the titlecompound as a solid (0.9 g, 117%): mp 197.2-199.1° C. ¹H NMR(acetone-d₆/300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J=2.7 Hz), 7.30 (d, 1H,J=2.4 Hz), 5.88 (q, 1H, J=7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J=7.5 Hz).FABLRMS m/z 307 (M+H). Anal. Calc'd for C₁₃H₁₀ClF₃O₃: C, 50.92; H, 3.29.Found: C, 51.00; H, 3.23.

EXAMPLE 30

[0848]

[0849] 6-Chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0850] 7-Phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(Example 26) was converted to the title compound by a procedure similarto that described in Example 29: mp 185.3-187.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.68 (s, 1H), 7.47 (m, 5H), 7.06 (s,1H), 5.87 (q, 1H, J=6.9 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd forC₁₇H₁₀ClF₃O₃: C, 57.56; H, 2.84. Found: C, 58.27; H, 3.11.

EXAMPLE 31

[0851]

[0852] 6,7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0853] 3,4-Dichlorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 196.1-198.3° C. ¹HNMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.74 (s, 1H), 7.30 (s, 1H), 5.88(q, 1H, J=6.9 Hz). FABLRMS m/z 314 (M+H). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃:C, 42.20; H, 1.61. Found: C, 42.31; H, 1.65.

EXAMPLE 32

[0854]

[0855] 6,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0856] 3,5-Dichlorosalicylaldehyde was converted to the title compoundby a procedure similar to that described in Example 11, Steps 2 & 3: mp212.8-216.8° C. ¹H NMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.41 (d, 1H, J=2.4Hz), 7.18 (d, 1H, J=2.2 Hz), 5.82 (q, 1H, J=6.7 Hz). FABLRMS m/z 311(M−H). FABHRMS m/z 312.9644 (M+H, Calc'd 312.9646). Anal. Calc'd forC₁₁H₅F₃Cl₂O₃: C, 42.20; H, 1.61. Found: C, 42.50; H, 1.71.

EXAMPLE 33

[0857]

[0858] 6,8-Dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0859] 3,5-Dibromosalicylaldehyde was converted to the title compound bya procedure similar to that described in Example 1: mp 225-226° C. 1HNMR (CD₃OD/300 MHz) 7.76 (s, 1H), 7.74 (d, 1H, J=2.2 Hz), 7.55 (d, 1H,J=2.2 Hz), 5.91 (q_(H−F), 1H, J=7.2 Hz). FABHRMS m/z 400.8648 (M+H⁺,Calc'd 400.8636). Anal. Calcd for C₁₁H₅Br₂F₃O₃: C, 32.87; H, 1.25.Found: C, 33.47; H, 1.38.

EXAMPLE 34

[0860]

[0861] 6,8-Dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0862] 4,6-Dimethoxysalicylaldehyde was converted to the title compoundby a procedure similar to that described in Example 1: mp 215-217° C. ¹HNMR (CD₃OD/300 MHz) 7.95 (s, 1H), 6.18-6.20 (m, 2H), 5.65 (q_(H−F), 1H,J=7.2 Hz), 3.87 (s, 1H), 3.81 (s, 1H). FABHRMS m/z 303.0497 (M−H⁺,Calc'd 303.0380). Anal. Calc'd for C₁₃H₁₁F₃O₅: C, 51.33; H, 3.64. Found:C, 51.19; H, 3.71.

EXAMPLE 35

[0863]

[0864] Ethyl 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

[0865] Step 1. Preparation of ethyl6-nitro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

[0866] A mixture of 5-nitrosalicylaldehyde (4.80g, 28.7 mmol) and ethyl4,4,4-trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was warmedto 60° C. and treated with anhydrous K₂CO₃ (3.90 g, 28.9 mol). Thesolution was maintained at 60° C. for 20 hours, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over anhydrous MgSO₄,filtered and concentrated in vacua to afford an oil. The oil wasdissolved in diethyl ether (5 mL). Hexanes was added until the solutionbecame cloudy. Upon standing at room temperature overnight the ester wasobtained as yellow crystals (0.856 g, 7% yield). This material was ofsufficient purity to be used in subsequent steps without furtherpurification. ¹H NMR (CDCl₃/300 MHz) 8.15-8.19 (m, 2H), 7.74 (s, 1H),7.09 (d, 1H, J=8.9 Hz), 5.81 (q, 1H, J=5.8 Hz), 4.29-4.39 (m, 2H), 1.35(t, 3H, J=6.0 Hz),

[0867] Step 2. Preparation of ethyl6-amino-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[0868] The ester (Step 1)(0.345 g, 1.08 mmol) was stirred in ethanol(10.0 mL) with 10% palladium on charcoal (15 mg) with hydrogen at 1atmosphere for 1 hour. The catalyst was removed by filtration and thesolvent removed in vacuo to afford the title compound as anorange-yellow solid (0.298 g, 95%): mp 111-115° C. (CD₃0D/300 MHz) 7.69(s, 1H), 6.69-6.74 (m, 3H), 5.65 (q_(H−F), 1H, J=7.2 Hz), 4.26-4.37 (m,2H), 1.34 (t, 3H, J=7 Hz). FABHRMS m/z 288.0860 (M+H⁺, C₁₃H₁₃F₃NO₃requires 288.0847). Anal. Calc'd for C₁₃H₁₂F₃NO₃: C, 54.36; H, 4.21; N,4.88. Found: C, 54.46; H, 4.27; N, 4.83.

EXAMPLE 36

[0869]

[0870] 6-Amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0871] Ethyl 6-amino-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 35, Step 2) was hydrolyzed to the carboxylic acid (titlecompound) by a procedure similar to that described in Example 1, Step 2:mp 126-133° C.

[0872]¹H NMR (CD₃OD/300 MHz) 6.81-6.90 (m, 3H), 5.66 (q_(H−F), 1H, J=7.2Hz). FABHRMS m/z 260.0535 (M+H⁺, C₁₁H₉F₃NO₅ requires 260.0534).

EXAMPLE 37

[0873]

[0874] 6-Nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0875] Ethyl 6-nitro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 35, Step 1) was hydrolyzed to the carboxylic acid (titlecompound) by a procedure similar to that described in Example 1, Step 2:mp 187-189° C.

[0876]¹H NMR (CD₃OD/300 MHz) 8.34 (d, 1H, J=2.6 Hz), 8.27 (dd, 1H,J=8.7, 2.6 Hz), 7.90 (s, 1H), 7.09 (s, 1H, J=8.7 Hz), 5.81 (q_(H−F), 1H,J=7.2 Hz). EIHRMS m/z 289.0177 (Calc'd 289.0198). Anal. Calc'd forC₁₁H₆F₃NO₅: C, 45.69; H, 2.09; N 4.84 Found: C, 45.71; H, 2.08; N 4.75.

EXAMPLE 38

[0877]

[0878] 6-Chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0879] 4-Chloro-2-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 231.9-233.2° C.

[0880]¹H NMR (CDCl₃/300 MHz) 7.76 (s, 1H), 7.19 (d, 1H, J=1.8 Hz), 7.09(d, 1H, J=2.4 Hz), 5.72 (q, 1H, J=6.9 Hz), 2.24 (s, 3H). ¹⁹F NMR(CDCl₃/282 MHz) −79.2 (d, J=6.5 Hz). FABLRMS m/z 299 (M+Li). FABHRMS m/z293.0196 (M+H, Calc'd 293.0192). Anal. Calc'd for C₁₂H₈ClF₃O₃: C, 49.25;H, 2.76. Found: C, 49.37; H, 2.86.

EXAMPLE 39

[0881]

[0882] 8-Chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0883] 2-Chloro-4-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 226.4-227.4° C.

[0884]¹H NMR (CDCl₃/300 MHz) 7.79 (s, 1H), 7.23 (d, 1H, J=1.4 Hz), 6.97(d, 1H, J=1.4 Hz), 5.77 (q, 1H, J=6.8 Hz), 2.29 (s, 3H). ¹⁹F NMR(CDCl₃/282 MHZ) −79.1 (d, J=7.3 Hz). FABLRMS m/z 291 (M−H). EIHRMS m/z292.0118 (M+, C₁₂H₈ClF₃O₃ Calc'd 292.0114).

EXAMPLE 40

[0885]

[0886] 8-Chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0887] 2-Chloro-4-methoxyphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 204.5-206.9° C.

[0888]¹H NMR (CDCl₃/300 MHz) 7.78 (s, 1H), 6.98 (d, 1H, J=2.8 Hz), 6.71(d, 1H, J=2.8 Hz), 5.74 (q, 1H, J=6.9 Hz), 3.79 (s, 3H). FABLRMS m/z 326(M+NH₄). EIHRMS m/z 308.0053 (M+Calc'd 308.0063). Anal. Calc'd forC₁₂H₈ClF₃O₄: C, 46.70; H, 2.61. Found: C, 46.60; H, 2.68.

EXAMPLE 41

[0889]

[0890] 6,8-Difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0891] 2,4-Difluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 207-211° C. ¹H NMR(CDCl₃) 7.63 (s, 1H), 6.89−6.72 (m, 2H), 5.69 (q, 1H, J=6.7 Hz). Anal.Calc'd for C₁₁H₅O₃F₅: C, 47.16; H, 1.80. Found: C, 47.28; H, 1.87.

EXAMPLE 42

[0892]

[0893] 6-Bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0894] 4-Bromo-2-chlorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 220.7-221.7° C. ¹HNMR (CDCl₃) 7.58 (s, 1H), 7.44 (d, 1H, J=2.2 Hz), 7.22 (d, 1H, J=2.2Hz), 5.74 (q, 1H, J=6.8 Hz). Anal. Calc'd for C₁₁H₅O₃F₃BrCl: C, 36.96;H, 1.41. Found: C, 37.03; H, 1.44.

EXAMPLE 43

[0895]

[0896] 8-Bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0897] 2-Bromo-4-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp >300° C. ¹H NMR(CDCl₃) 7.58 (s, 1H), 7.22 (dd, 1H, J=6.3, 3 Hz), 6.88 (dd, 1H, J=6.1,3.1 Hz), 5.72 (q, 1H, J=6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C, 38.74;H, 1.48. Found: C, 38.82; H, 1.56.

EXAMPLE 44

[0898]

[0899] 8-Bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0900] 2-Bromo-4-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 237-238° C. ¹H NMR(CDCl₃) 7.59 (s, 1H), 7.27 (m, 1H), 6.91 (d, 1H, J=1.4 Hz), 5.69 (q, 1H,J=6.9 Hz), 2.20 (s, 3H). Anal. Calc'd for C₁₂H₈O₃F₃Br: C, 42.76; H,2.39. Found: C, 43.34; H, 2.56.

EXAMPLE 45

[0901]

[0902] 8-Bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0903] 2-Bromo-5-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 221.7-223.3° C. ¹HNMR (CDCl₃) 7.81 (s, 1H), 7.38 (dd, 1H, J=7.3, 5.8 Hz), 6.58 (t, 1H,J=8.9 Hz), 5.71 (q, 1H, J=6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C,38.74; H, 1.48. Found: C, 38.70; H, 1.54.

EXAMPLE 46

[0904]

[0905] 6-Chloro-B-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0906] 4-Chloro-2-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 190.8-193.0° C.

[0907]¹H NMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.19 (d of d, 1H, J=2.2 and9.7 Hz), 7.07 (t, 1H, J=1.8 Hz), 5.76 (q, 1H, J=6.7 Hz). FABLRMS m/z 295(M−H). EIHRMS m/z 295.9876 (M+Calc'd 295.9863). Anal. Calc'd forC₁₁H₅ClF₄O₃: C, 44.54; H, 1.70. Found: C, 44.36; H, 1.85.

EXAMPLE 47

[0908]

[0909] 6-Bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0910] 4-Bromo-2-methoxysalicylaldehyde was converted to the titlecompound by a procedure similar to that described in Example 1; dec. at244° C. ¹H NMR (CD₃OD/300 MHz) 7.71 (s, H), 7.18 (d, 1H, J=2.2 Hz), 7.11(d, 1H, J=2.2 Hz), 5.77 (q_(H−F), 1H, J=7.2 Hz), 3.84 (s, 3H). FABLRMSm/z 351 (m−H). Anal. Calc'd for C₁₂H₈BrF₃O₅: C, 40.82; H, 2.28. Found:C, 40.83; H, 2.30.

EXAMPLE 48

[0911]

[0912]7-(N,N-Diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0913] 4-(N,N-Diethylamino)salicylaldehyde was converted to the titlecompound by a procedure similar to that described in Example 1: mp214.4-215.4° C. ¹H NMR (CD₃OD/300 MHz) 7.67 (s, 1H), 7.06 (d, 1H, J=8.6Hz), 6.34 (dd, 1H, J=8.6, 2.3 Hz), 5.60 (q_(H−F), 1H, J=7.2 Hz), 3.38(q, 4H, J=7.1 Hz), 1.16 (t, 6H, J=7.1 Hz). ESLRMS m/z 316 (M+H). FABHRMSm/z 316.1145 (M+H⁺, Calc'd 316.1161). Anal. Calc'd for C₁₅H₁₆F₃NO₃: C,57.14; H, 5.11; N, 4.44. Found: C, 57.14; H, 5.08; N, 4.44.

EXAMPLE 49

[0914]

[0915]6-[[(Phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0916] Step 1. Preparation of ethyl6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

[0917] Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2)(6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour,the solution was warmed to room temperature and stirred for 16 hours.The solution was added dropwise onto ice (500 mL) with vigorous stirringand extracted with diethyl ether (2×250 mL). The ether layers werecombined, washed with water (2×250 mL), saturated sodium bicarbonate(2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and thesolution was dried over sodium sulfate. The solvent was removed in vacuoto afford the ester as a yellow solid (7.41 g, 87%): mp 97.2-98.4° C. ¹HNMR (CDCl₃, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (q_(H−F), 1H, J=7.2 Hz),4.28-4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li⁺).

[0918] Step 2. Preparation of ethyl6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

[0919] The sulfonyl chloride from Step 1 (451.0 mg, 1.22 mmol) andbenzylamine (600 mg, 5.62 mmol) were mixed in diethyl ether (25 mL) for1 hour at room temperature. The solution was washed with 1N HCl (2×25mL), saturated sodium bicarbonate (2×25 mL), and brine (2×25 mL). Thesolution was dried over sodium sulfate and dried in vacuo. Theaminosulfonyl was obtained by crystallization from hexanes (431 mg,84%): mp 128.2-131.9° C. ¹H NMR (CDCl₃, 300 MHz) 7.76 (dd, 1H, J=8.4,2.2. Hz), 7.70 (d, 1H, J=2.2 Hz), 7.67 (s, 1H), 7.12-7.30 (m, 5H), 7.05(d, 1H, J=8.4 Hz), 5.78 (q_(H−F), 1H, J=7.2 Hz), 4.68 (m, 2H), 4.19-4.32(m, 2H), 1.37 (t, 3H, J=7.0 Hz). FABLRMS m/z 442 (M+H⁺). FABHRMS m/z442.0936 (M+H⁺, C₂₀H₁₉F₃NO₅S Calc'd 442.0916).

[0920] Step 3. Preparation of6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

[0921] The acid was converted from the ester (step 2) via the methodsimilar to that described in Example 1, step 2: mp 223.3-224.4° C. ¹HNMR (CD₃OD/300 MHz) 7.31-7.80 (m, 3H), 7.15-7.25 (m, 5H), 7.06 (d, 1H,J=8.3 Hz), 5.87 (q_(H−F), 1H, J=7.2 Hz), 4.11 (s, 2H). FABLRMS m/z 420(M+Li⁺). FABHRMS m/z 414.0589 (M+H⁺ Calc'd 414.0623). Anal. Calc'd forC₁₈H₁₄F₃NO₅S: C, 52.30; H, 3.41; N, 3.39. Found: C, 5.16; H, 3.44; N,3.32.

EXAMPLE 50

[0922]

[0923]6-[(Dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0924] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 201.2-202.5° C. ¹H NMR (CD₃OD/300 MHz) 7.90(s, 1H), 7.82 (d, 1H, J=2.2 Hz), 7.76 (dd, 1H, J=8.6, 2.2 Hz), 7.19 (d,1H, J=8.6 Hz), 5.91 (q_(H−F), 1H, J=7.2 Hz), 2.70 (s, 6H). FABLRMS m/z352 (M+H⁺). FABHRMS m/z 352.0466 (M+H⁺ Calc'd 352.0467). Anal. Calc'dfor C₁₃H₁₂F₃NO₅S: C, 44.45; H, 3.44; N, 3.99. Found: C, 4.42; H, 3.45;N, 3.96.

EXAMPLE 51

[0925]

[0926] 6-Aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0927] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 187.9-189.8° C. ¹H NMR (CD₃OD/300 MHz)7.58-7.88 (m, 3H), 7.12 (d, J=8.3 Hz), 5.87 (q_(H−F), 1H, J=7.2 Hz).FABLRMS m/z 324 (M+H⁺). FABHRMS m/z 324.0156 (M+H⁺ Calc'd 324.0154).Anal. Calc'd for C₁₁H₈F₃NO₅S * 0.74 H₂O: C, 39.26; H, 2.84; N, 4.16.Found: C, 39.33; H, 2.82; N, 4.11.

EXAMPLE 52

[0928]

[0929]6-(Methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0930] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 207.6-208.6° C. ¹H NMR (CD₃OD/300 MHz)7.83-7.97 (m, 3H), 7.19 (d, 1H, J=8.5 Hz), 5.91 (q_(H−F), 1H, J=7.2 Hz),3.11 (s, 3H). FABLRMS m/z 338 (M+H⁺). FABHRMS m/z 338.0331 (M+H⁺ Calc'd338.0310). Anal. Calc'd for C₁₂H₁₁F₃NO₅S: C, 42.73; H, 2.99; N, 4.15.Found: C, 42.91; H, 3.06; N, 4.04.

EXAMPLE 53

[0931]

[0932]6-[(4-Morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0933] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 215.2-219.3° C. ¹H NMR (CD₃OD/300 MHz) 7.88(S, 1H), 7.81 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H, J=8.6, 2.2 Hz), 5.90(q_(H−F), 1H, J=7.2 Hz), 3.54-3.70 (m, 4H), 2.94-2.97 (m, 4H). FABLRMSm/z 394 (M+H⁺). FABHRMS 394.0567 (M+H⁺, C₁₅H₁₅F₃NO₆S Calc'd 394.0572).

EXAMPLE 54

[0934]

[0935]6-[(1,1-Dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0936] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 229.3-233.5° C. ¹H NMR (CD₃OD/300 MHz)7.82-7,87 (m, 3H), 7.12 (d, 1H, J=8.6 Hz), 5.87 (q_(H−F), 1H, J=7.2 Hz),1.18 (s, 9H). FABLRMS m/z 380 (M+H⁺). Anal. Calc'd for C₁₅H₁₆F₃NO₅S: C,47.49; H, 4.25; N, 3.69. Found: C, 47.95; H, 4.48; N, 3.55.

EXAMPLE 55

[0937]

[0938]6-[(2-Methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0939] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 190.6-192.4° C. ¹H NMR (CD₃OD/300 MHz)7.77-7.84 (m, 3H), 7.13 (d, 1H, J=8.4 Hz), 5.86 (q_(H−F), 1H, J=7.2 Hz),2.64 (d, 2H, J=6.8 Hz), 1.66 (sept, 1H, J=6.6 Hz), 0.84 (d, 6H, J=6.6Hz). FABLRMS m/z 380 (M+H⁺). Anal. Calc'd for C₁₅H₁₆F₃NO₅S: C, 47.49; H,4.25; N, 3.69. Found: C, 47.61; H, 3.34; N, 3.55.

EXAMPLE 56

[0940]

[0941] 6-Methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0942] Step 1. Preparation of6-chlorosulfonyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[0943] To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution waswarmed to room temperature and stirred for 16 hours. The resultingsolution was added dropwise over ice (100 mL) with two diethylether(2×75 mL) extractions. The diethyl ether layers were combined,washed with water (2×75 mL), and brine (2×75 mL, dried over sodiumsulfate and concentrated in vacuo. The resulting solids were trituratedwith hexane-ethyl acetate (9:1, 100 mL). The6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid wasisolated as a white solid: mp 169-174.

[0944]¹H NMR (CD₃OD/300 MHz) 8.18 (d, 1H, J=2.7 Hz), 8.06 (dd, 1H,J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 6.00 (q, 1H, J=6.6Hz). EIHRMS m/z 324.9977 (M+, Calcd 324.9994).

[0945] Step 2. Preparation of6-methylsulfonyl-2-(trifluoromentyl)-2H-1-benzopyran-3-carboxylic acid

[0946] A slurry of the chlorosulfonyl intermediate (Example 49, Step1)(493 mg, 1.44 mmol), sodium bicarbonate (362 mg, 4.32 mmol), andsodium bisulfite (181 mg, 1.44 mmol) in water (1.5 mL)was heated to 60°C. for 1.5 h, followed by the addition of bromoacetic acid (212 mg, 1.55mmol). The resulting suspension was heated to reflux, followed by theaddition of sodium hydroxide solution (50% NaOH soln., 0.10 mL) andwater (3.0 mL). The solution was reluxed for 8 hours, cooled to roomtemperature, and acidified to pH 1 with 1N aqueous hydrochloric acid.The solution was extracted with ethyl acetate (2×25 mL). The combinedethyl acetate layers were washed with 1N aqueous hydrochloric acid (2×25mL), water (2×25 mL), and brine (2×25 mL), dried over sodium sulfate,filtered and concentrated in vacuo yielding the title compound as an offwhite solid. (231 mg, 50% yield): mp 208.3-212.4° C. ¹H NMR (CD₃OD, 300MHz) 7.97 (d, 1H, 2.2 Hz), 7.91 (1H, dd, J=8.7, 2.2 Hz), 7.19 (d, 1H,J=8.7 Hz), 5.91 (q_(H−-F), 1H, J=7.2 Hz), 3.11 (s, 1H) HRLRMS m/z 321(M−H) FABLRMS m/z 321 (M−H). Anal. Calc'd for C₁₂H₉F₃O₅S*0.61 H₂O: C,43.26; H, 3.09. Found: C, 43.24; H, 3.09.

EXAMPLE 57

[0947]

[0948]8-Chloro-6-[[(phonylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0949] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 167.0-173.8° C. ¹H NMR (CD₃OD/300 MHz) 7.78(s, 1H), 7.72 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=2.0 Hz). 7.44 (s, 1H),7.15-7.23 (m, 5H), 6.01 (q_(H−F), 1H, J=7.2 Hz),4.08-4.15 (m, 2H).FABLRMS m/z 454 (M+Li+). Anal. Calc'd for C₁₆H₁₃ClF₃NO₅S: C, 48.28; H,2.93; N, 3.13. Found: C, xx; H, xx; N, xx.

EXAMPLE 58

[0950]

[0951]6-N,N-Diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0952] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 238-240° C. ¹H NMR (CD₃OD/300 MHz) 7.88 (s,1H), 7.85 (d, 1H, J=2.2 Hz), 7.79 (dd, 1H, J=8.5, 2.2 Hz), 7.14 (d, 1H,J=8.5 Hz), 5.88 (q_(H−F), 1H, J=7.2 Hz), 3.24 (q, 2H, J=7.3 Hz), 1.11(t, 3H, J=7.3 Hz). FABHRMS m/z 380.0763 (M+H+, Calc'd 380.0780). Anal.Calc'd for C₁₅H₁₆F₃NO₄S: C, 47.49; H, 4.25; H, 3.69. Found: C, 47.62; H,4.30; N, 3.72.

EXAMPLE 59

[0953]

[0954] 6-Phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0955] Step 1. Preparation of ethyl6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

[0956] 2-Trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 10)(1.32 g, 4.85 mmol) was cooled to 0° C. in dichloromethane (50 mL).Aluminum chloride (2.58 g, 19.5 mmol) was added and a dark red solutionresulted. A solution of phenylacetyl chloride (1.8 g, 12.1 mmol) indichloromethane (10.0 mL) was added dropwise over 40 minutes. Thesolution was warmed to room temperature and stirred for 16 hours. Thesolution was poured onto ice (200 mL) and extracted with diethyl ether(2×100 mL). The diethyl ether layers were combined, extracted with water(1×100 mL), 1 N HCl (2×100 mL), and saturated sodium bicarbonate (3×100mL). Hexanes (20 mL) were added and the solution was extracted withbrine (1×100 mL). The solution was dried over sodium sulfate and solventwas removed in vacuo. The crude ester was purified by flashchromatography over silica gel (with ethyl acetate as eluant) to affordthe ester that was crystllized from diethyl ether/hexanes (830 mg, 44%):mp 136.2-138.0° C. ¹H NMR (CDCl₃/300 MHz) 7.98 (dd, 2H, J=8.4, 2.0 Hz),7.90 (d, 1H, J=2.0 Hz), 7.29 (s, 1H), 7.22-7.38 (m, 5H), 7.02 (d, 1H,J=8.4 Hz), 5.75 (q_(H−F), 1H, J=7.2 Hz), 4.25-4.40 (m, 2H), 4.21 (s,2H), 1.34 (t, 3H, J=7.0 Hz). FABLRMS m/z 391(M+H⁺).

[0957] Step 2. Preparation of6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[0958] The acid was converted from the ester (Step 1) via a methodsimilar to that described in Example 1, step 2: mp 159.0-164.0° C. ¹HNMR (CD₃OD/300 MHz) 8.04-8.16 (m, 3H), 7.87 (s, 1H), 7.05-7.30 (m, 5H),5.86 (q_(H−F), 1H, J=7.2 Hz), 4.31 (s, 2H). FA (M+H⁺). Anal. Calc'd forC₁₉H₁₃F₃O₄*0.29 H₂0: C, 62.08; H, 3.73. Found: C, 62.04; H, 4.03.

EXAMPLE 60

[0959]

[0960]6-(2,2-Dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0961] The title compound was prepared by a similar procedure to thatdescribed in Example 59: mp 198-200° C. ¹H NMR (CD₃OD/300 MHz) 7.98-8.06(m, 2H), 7.88 (s, 1H), 7.07 (d, 1H, J=8.9 Hz), 5.86 (q_(H−F), 1H, J=7.2Hz), 2.88 (s, 2H), 1.05 (s, 9H). FABHRMS m/z 343.1175 (M+H⁺, C₁₇H₁₈F₃O₄requires 343.1157). Anal. Calc'd for C₁₇H₁₇F₃O₄: C, 59.65; H, 5.01.Found: C, 59.70; H, 4.97.

EXAMPLE 61

[0962]

[0963]6,8-Dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0964] Step 1: Preparation of ethyl7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylate

[0965] 4-Methoxysalicylaldehyde (2.38 g, 15.64 mmol), K₂CO₃ (2.16 g,15.64 mmol) and ethyl 4,4,4-trifluorocrotonate (2.8 mL, 3.16 g, 18.77mmol) were dissolved in DMF (10 mL). The reaction was stirred at roomtemperature for 24 hours, diluted with water and extracted with Et₂O.The combined Et₂O phases were washed with water, dried over MgSO₄,filtered and concentrated in vacuo yielding an oil. Trituration withhexanes induced crystallization. Collection of the solid by vacuumfiltration yielded the ester as a light brown crystalline solid (1.80 g,38%): mp 78-80° C. ¹H NMR (CDCl₃/300 MHz) δ7.69 (s. 1H), 7.14 (d, 1H,J=8.1 Hz), 6.59−6.50 (m, 2H), 5.68 (q, 1H, J=7.1 Hz), 4.39−4.24 (m, 2H),3.82 (s, 3H), 1.34 (t, 3H, J=7.3 Hz). FABLRMS m/z 303 (M+H). FABHRMS m/z303.0849 (M+H Calc'd 303.0844). Anal. Calc'd for C₁₄H₁₃F₃O₄: C, 55.63;H, 4.34. Found: C, 55.47; H, 4.31.

[0966] Step 2. Preparation of ethyl6,8-dichloro-7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylate

[0967] Chlorine gas (excess) was added to a stirred solution of theester (Step 1) (1.35 g, 4.47 mmol) in HOAc (30 mL) until the yellowcolor persisted. After 20 minutes, the reaction was sparged withnitrogen causing the reaction to become straw colored. Zinc (0.86 g,13.40 mmol) was added to this solution with vigorous stirring. After 45minutes, additional zinc (0.86 g, 13.40 mmol) was added and the reactionwas stirred overnight. The crude mixture was diluted with EtOH andfiltered through diatomaceous earth. The filtrate was concentrated invacuo yielding a crystalline mass. This solid was dissolved in EtOAc,washed with 2N HCl, brine, dried over MgSO₄, filtered and concentratedin vacuo yielding an oil. The oil was dissolved in a minimum ofisooctane, inducing crystallization. Vacuum filtration of the suspensionyielded tan needles (1.078 g) which were recrystallized from isooctaneyielding the dichloro ester as tan crystals (0.71 g, 43%) of suitablepurity to use in the next step: mp 113.3-115.1° C. ¹H NMR(acetone-d₆/300 MHz) 7.88 (s, 1H), 7.63 (s, 1H), 6.02 9q, 1H, J=6.8 Hz),4.38−4.22 (m, 2H), 3.93 (s, 3H), 1.31 (t, 3H, J=7.1 Hz).

[0968]¹⁹F NMR (acetone-d₆/282 MHz) −80.00 (d, J=7.2 Hz).

[0969] Step 3: Preparation of6,8-dichloro-7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylicacid.

[0970] To a stirred solution of the dichloro ester from Step 2 (0.686 g,1.848 mmol) in THF (10 mL) and EtOH (3 mL) was added NaOH (0.81 mL of2.5 M aqueous solution, 2.03 mmol) in one portion. After stirringovernight the reaction was partially concentrated, diluted with H₂O andwashed with diethyl ether. The resulting aqueous phase was sparged withnitrogen and acidified with 2N HCl solution causing the solution tobecome turbid. Filtration of this suspension yielded the title compoundas a white powder (0.559 g, 88%): mp 195.6-199.1° C. ¹H NMR (CDCl₃/300MHz) 7.90 (s, 1H), 7.64 (s, 1H), 6.01 (q, 1H, J=6.8 Hz), 3,94 (s, 3H).¹⁹F NMR (CDCl₃/282 MHz) −79.63 (d, J=7.1 Hz). FABLRMS m/z 349 (M+Li).EIHRMS m/z 341.9681 (M+, Calc'd 341.9673). Anal. Calc'd forC₁₂H₇Cl₂F₃O₄: C, 42.01; H, 2.06. Found: C, 41.76; H, 2.14.

EXAMPLE 62

[0971]

[0972] 2-Trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid

[0973] Step 1. Preparation of ethyl2-trifluoromethyl-3H-naphthopyran-carboxylate.

[0974] A mixture of 2-hydroxy-1-naphthaldehyde (8.6 g, 0.050 mol) andethyl 4,4,4-trifluorocrotonate (9.2 g, 0.055 mol) dissolved in anhydrousdimethylformamide (DMF) and treated with anhydrous K₂CO₃ (13.8 g, 0.100mol). The solution was maintained at room temperature for 50 hours anddiluted with water. The solution was extracted with ethyl acetate, andthe combined extracts were washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to afford 4.8 g of an oil. Theoil was purified by HPLC, eluting with hexanes:ethyl acetate (30:1). Theappropriate fractions were concentrated to afford 1.6 g (10%) of thenapthopyran ester as a yellow solid.

[0975] Step 2. Preparation of2-trifluoromethyl-3H-naphthopyran-carboxylic acid. A solution of theester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanoland 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10mL, 25 mmol) and stirred at room temperature for 16 hours. The reactionmixture was acidified with 1.0 N HCl, whereupon a solid formed that wasisolated by filtration. The solid was washed with 20 mL of water toafford 0.7 g (95%) of the title compound as a yellow solid: mp245.9-248.6° C. ¹H NMR (acetone-d₆/300 MHz) 8.57 (s, 1H), 8.28 (d, 1H,J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H),7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (q_(H−F), 1H, J=7.2 Hz). FABHRMSm/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C₁₅H₉O₃F₃+3.31%H₂O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.

EXAMPLE 63

[0976]

[0977] 2-Trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid

[0978] 2-Hydroxy-napth-1-aldehyde was converted to the title compound bya procedure similar to that described in Example 1: mp 244.7-249.8° C.¹H NMR (CDCl₃/300 MHz) 8.61 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.90 (d,1H, J=8.9 Hz), 7.82 (d, 1H, J=8.3 Hz), 7.63 (t, 1H, J=8.1 Hz), 7.47 (t,1H, J=8.1 Hz), 7.23 (d, 1H, J=9.1 Hz), 5.84 (q, 1H, J=6.8 Hz). ¹⁹F NMR(CDCl₃/282 MHz) −79.56 (d, J=7.3 Hz). FABLRMS m/z 295 (M+H). FABHRMS m/z295.0560 (M+H, Calc'd 295.0582). Anal. Calc'd for C₁₅H₉F₃O₃: C, 61.23;H, 3.08. Found: C, 60.85; H, 3.12.

EXAMPLE 64

[0979]

[0980] 2-Trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid

[0981] 3-Hydroxynapthalene-2-carboxylic acid was converted to3-hydroxynapthal-carboxaldehyde by a similar edure to that described inExample 24, Steps 1 & 2. The 3-hydroxynapthalene-2-carboxaldehyde wasconverted to the title compound by a procedure similar to that describedin Example 1: mp decompose >300° C. ¹H NMR (CD₃OD/300 MHz) 7.99 (s, 1H),7.90 (s, 1H), 7.84 (d, 1H, J=8.2 Hz), 7.74 (d, 1H, J=8.2 Hz), 7.50 (t,1H, J=8.2 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.34 (s, 1H), 5.77 (q, 1H, J=6.6Hz). EIHRMS m/z 294.0474 (M+, Calc'd 294.0504).

EXAMPLE 65

[0982]

[0983] 6-Chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid

[0984] Step 1: Synthesis of 5-chloro-thiosalicylaldehyde.

[0985] Tetramethylethylenediamine (TMEDA)(10.44 mL, 8.035 g, 69.15 mmol)was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15mmol) and the solution was chilled to 0° C. A solution of4-chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 mL) was addedwith stirring over 1 hour. The resulting tan slurry was stirredovernight at room temperature, chilled to 0° C., and DMF (2.94 mL, 2.78g, 38.03 mmol) was added via syringe over 2 minutes. The resulting gummyslurry was stirred at room temperature for 30 hours and became a powderysuspension. A mixture of 2 N HCl and ice was added to the reactionmixture until the pH became acidic (pH=1). During this addition, themixture warmed and became first red and then pale yellow. This mixturewas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated in vacuoyielding a clear red-brown oil. This oil was triturated with hexanesyielding a red-brown semisolid. This semisolid was purified by plugflash chromatography over silica gel, eluting with 1:1,hexanes:dichloromethane to afford 5-chloro-thiosalicylaldehyde (0.858 g,14%) as an intensely yellow solid suitable for use without furtherpurification.

[0986] Step 2: Preparation of ethyl6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylate.

[0987] 5-Chloro-thiosalicylaldehyde (Step 1) (0.84 g, 4.86 mmol) wasadded to DMF (3 mL) and ethyl 4,4,4-trifluorocrotonate (1.10 mL, 1.22g). With stirring, K₂CO₃ (0.67 g, 4.86 mmol) was added causing thereaction to become a deep red. After stirring overnight at roomtemperature, the reaction was diluted with diethyl ether and washed withwater, saturated NaHCO₃ solution, aqueous KHSO₄ solution (0.25 M),brine, dried over MgSO₄, filtered and concentrated in vacuo yielding anoil. The oil was purified by flash chromatography (5:1; hexanes: ethylacetate) yielding upon concentration ethyl6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylate as abright orange solid (0.492 g, 31%): mp 94.6-97.4° C. ¹H NMR (acetoned₆/300 MHz) δ8.01 (s, 1H), 7.71 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=8.5Hz), 7.44 (d of d, 1H, J=2.3, 8.3 Hz), 5.07 (q, 1H, J=8.5 Hz), 4.42−4.23(m, 2H), 1.35 (t, 3H, J=7.1 Hz). FABLRMS m/z 329 (M+Li).

[0988] Step 3: Preparation of6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylic acid

[0989] To a stirred solution of the ester from Step 2 (0.413 g, 1.280mmol) in THF: EtOH : H₂O (7:2:1, 10 mL) was added NaOH solution (0.56 mLof 2.5 N solution, 1.408 mmol) with stirring. After stirring overnight,the reaction was partially concentrated in vacua to remove the organicsolvents, diluted with H₂O and washed with several portions of diethylether. Acidification of the stirred aqueous phase with concentrated HClcaused precipitation of a flocculent yellow precipitate. Vacuumfiltration of the suspension yielded6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2H-3-carboxylic acid as ayellow powder (0.25 g, 66%): mp 188.8-198.7° C. ¹H NMR (acetone d₆/300MHz) δ8.02 (s, 1H), 7.71 (d, 1H, J=2.22 Hz), 7.50 (d, 1H, J=8.5 Hz),7.44 (d of d, 1 H, J=2.2, 8.5 Hz), 5.05 (q, 1H, J=8.6 Hz).

[0990]¹⁹F NMR (Acetone d₆/282 MHz) d −75.22 (d, J=8.7 Hz). FABLRMS m/z301 (M+Li); ESLRMS (neg. ion) m/z 293 (M−H).

EXAMPLE 66

[0991]

[0992] (S)-6-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[0993] To a solution of6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 1,Step 2)(12.00 g, 43.07 mmol) and (S)(-)-α-methylbenzylamine (2.61g,-21.54 mmol) in methyl-tert-butyl ether (30 mL) was slowly addedn-heptane (200 mL) until the mixture became cloudy. The mixture washeated (steam bath) to boiling and set aside for 24 h during which timecrystals formed. Filtration of the suspension yielded a crystallineproduct (5.5 g) which was recrystallized from methyl-tert-butyl ether(30 mL) and n-heptane (200 mL) yielding upon filtration a white solid(3.1 g). This solid was dissolved in EtOAc (100 mL) and washed with 1 Nhydrochloric acid (50 mL) and brine (2×50 mL), dried over MgSO₄ andconcentrated in vacuo yielding a white solid. Recrystallization of thissolid from methyl-t-butyl ether/n-heptane yielded the title compound asthe highly enriched isomer, a white solid (2.7 g, 45%): mp 126.7-128.9°C. ¹H NMR (CDCl₃/300 MHz) 7.78 (s, 1H), 7.3−7.1 (m, 3H), 6.94 (d, 1H,J=8.7 Hz), 5.66 (q, 1H, J=6.9 Hz). Anal. Calc'd for C₁₁H₆O₃F₃Cl: C,47.42; H, 2.17; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. This compoundwas determined to have an optical purity of greater than 90% ee.

[0994] Procedure for Determining Optical Purity

[0995] To a solution of the free acid (title compound) (0.005 g, 0.017mmol) in ethyl acetate (1.5 mL) in a test tube was added(trimethylsilyl)diazomethane (30 μL of 2.0 N solution in hexanes, 60mmol). The resulting yellow solution was warmed until the solution beganto gently boil and then was allowed to cool to room temperature andstand for 0.08 hours. With vigorous mixing, the solution was quenchedwith aqueous 1 N HCl (1.5 mL). The layers were separated and a sample ofthe ethyl acetate fraction (0.3 mL) was transferred to a vial,concentrated under a stream of nitrogen, was diluted with hexane (totalof 1 mL) and a sample (10 μL) analyzed by chiral chromatography. TheHPLC utilized a Daicel ChiralPak AD column eluting with 10%isopropanol-hexane at 0.5 mL/min using a UV detector set at 254 nM.

EXAMPLE 67

[0996]

[0997](S)-6-Trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[0998] To a solution of6-trifluormethoxy-2-(trifluoromethyl)-2H-1-benzop oxylic acid (Example16)(17.72 g, 54.00 mmol) and (−) cinchonidine (7.95 g, 27.04 mmol) inmethyl-tert-butyl ether (100 mL) heated on a steam-bath was addedn-heptane (200 mL). The mixture was heated on the steam bath to boilingand allowed to cool for 4 h during which time crystals formed.Filtration of the suspension yielded a crystalline solid (18.7 g). Thissolid was dissolved in 2-butanone (30 mL) followed by the addition ofn-heptane (500 mL). After standing for 16 hours, the resultingsuspension was filtered yielded a white solid (10.3 g). This solid wasdissolved in ethyl acetate (150 mL), washed with 1 N hydrochloric acid(100 mL) and brine (2×50 mL), dried over MgSO₄, filtered, andconcentrated in vacuo yielding a viscous yellow oil (5.2 g, 59%): ¹H NMR(acetone-d₆/300 MHz) 7.16 (s, 1H), 6.77 (d, 1H, J=2.7 Hz), 6.94 (d, 1H,J=8.7 Hz), 6.64 (m, 1H), 6.39 (d, 1H, J=8.7 Hz) 5.13 (q, 1H, J=7.2 Hz).Anal. Calc'd for C₁₂H₆O₄F₆: C, 43.92; H, 1.84; N, 0.0. Found: C, 43.79;H, 1.83; N, 0.0. This compound was determined to have an optical purityof greater than 90% ee. Chiral purity was determined as describe inExample 66.

EXAMPLE 68

[0999]

[1000](S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1001] To a solution of6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid (Example 8) (11.4 g, 34.1 mmol) and (S)(−)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was added n-heptane(200 mL) and the mixture set aside for 16 hours. The resultingsuspension was filtered yielding a solid (3.8 g). This solid wasrecrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yieldingupon filtration a white solid (3.0 g). This solid was dissolved in ethylacetate (100 mL) and washed with 1 N HCl (50 mL) and brine (2×50 mL),dried over MgSO, and concentrated in vacuo yielding a white solid. Thissolid was recrystallized from n-heptane yielding the title compound ofhigh optical purity as a crystalline solid (1.7 g, 30%): mp 175.4-176.9°C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H),5.83 (q, 1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C₁₅H₁₄O₃F₃Cl: C,53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl,10.65. This compound was determined to have an optical purity of greaterthan 90% ee. Chiral purity was determined as describe in Example 66.

EXAMPLE 69

[1002]

[1003]6-[[(2-Puranylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1004] The title compound was prepared by a similar procedure to thatdescribed in Example 49: mp 170-173° C. ¹H NMR (CD₃OD/300 MHz) 7.78 (s,1H), 7.66-7.76 (m, 2H), 7.18-7.22 (m, 1H), 7.00-7.08 (m, 1H), 6.12-6.18(m, 1H), 6.02-6.06 (m, 1H), 5.85 (q, 1H, J=7.0 Hz), 4.13 (s, 2H). EIHRMSm/z 403.0332 (M+, Calc'd 403.0337).

EXAMPLE 70

[1005]

[1006]6-[(Phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1007] The 2H-1-benzopyran-3-carboxylic acid was prepared analogous tothe procedure described in Example 56: mp 172-176° C. ¹H NMR (CD₃OD/300MHz) 7.73 (s, 1H), 7.43-7. 7.33 (m, 3H), 7.20-7.21 (m, 3H), 5.88 (q, 1H,J=7.0 Hz), 4.83 (s, 2H). EIHRMS m/z 398.0399 (M+, Calc'd 398.0436).

EXAMPLE 71

[1008]

[1009]6-[[(Phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1010] The 2H-1-benzopyran-3-carboxylic acid was prepared analogous tothe procedure described in Example 49: mp 187-190° C. ¹H NMR (CD₃OD/300MHz) 7.82 (s, 1H), 7.74-7.90 (m, 2H), 7.08-7.29 (m, 6H), 5.89 (q, 1H,J=6.8), 3.12 (t, 2H, J=7.3 Hz), 2.72 (t, J 7.3 Hz). EIHRMS m/z 427.0675(M+, Calc'd 427.0701)

EXAMPLE 72

[1011]

[1012] 7-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[1013] 4-Chlorosalicylic acid was converted to 3-chlorosalicylaldehydeby a procedure similar to that described in Example 24, Step The3-chlorosalicylaldehyde was converted to the title compound by aprocedure similar to Example 1: mp 175.2-177.6° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.12 (m, 2H),5.86 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 285.0114 (M+Li, Calc'd285.0118). Anal. Calc'd for C₁₁H₆ClF₃O₃: C, 47.42; H, 2.17; Cl, 12.72.Found: C, 47.54; H, 2.37; Cl, 12.85.

EXAMPLE 73

[1014]

[1015] 6-Chloro-8-iodo-2-(trifluoramethyl)-2H-1-benzopyran-3-carboxylicacid

[1016] Step 1. Preparation of 3-iodo-5-chlorosalicylaldehyde

[1017] N-Iodosuccinimide (144.0 g, 0.641 mole) was added to a solutionof 5-chlorosalicyaldehyde (100 g, 0.638 mole) in dimethylformamide (400mL). The reaction mixture was stirred for two days at room temperature.Additional N-iodosuccinimide (20 g, 0.089 mole) was added and thestirring was continued for an additional two days. The reaction mixturewas diluted with ethyl acetate (1 liter), washed with hydrochloric acid(300 mL, 0.1 N), water (300 mL), sodium thiosulfate (300 mL, 5%), andbrine (300 mL). It was dried over MgSO₄, and was concentrated to drynessto afford the desired aldehyde as a pale yellow solid (162 g, 90%): mp84.8-86.7° C. ¹H NMR (CDCl₃/300 MHz) 11.67 (s, 1H), 9.71 (s, 1H), 7.92(d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.6 Hz). FABLRMS m/z 281.0 (M−H).ESHRMS m/z 280.8851 (M−H, Calc'd. 280.88630).

[1018] Step 2. Preparation of ethyl6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

[1019] 5-Chloro-3-iodosalicylaldehyde (20 g, 70.8 mmol), ethyl4,4,4-trifluorocrotonate (17.85 g, 106 mmol), and triethylamine (14.33g, 142 mmol) were dissolved in DMSO (200 mL). The reaction mixture wasstirred at 90° C. for three days. The reaction mixture was poured intoethyl acetate (800 mL). It was extracted with 10% HCl (2×200 mL),saturated aqueous NaHCO₃ (2×200 mL), and water (2×200 mL). The ethylacetate phase was dried over MgSO₄, filtered and evaporated to yield abrown solid. It was then run through a plug of silica with ethylacetate-hexane (1:20). The solvent was evaporated to give a yellowsolid, that was recrystallized in hexane to afford the ester as a whitesolid (19.61 g, 64%): mp 92.1-93.9° C. ¹H NMR (CDCl₃/300 MHz) 7.71 (d,1H, J=2.2 Hz), 7.56 (s, 1H), 7.20 (d, 1H, J=2.2 Hz), 5.81 (q, 1H, J=6.7Hz), 4.37−4.29 (m, 2H), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 431.9 (M−H).EIHRMS m/z 431.9269 (M−H, Calc'd. 431.9237).

[1020] Step 3. Preparation of6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1021] The ester (Step 2) was converted to the acid by a proceduresimilar to the method described in Example 1, Step 2: mp 220-223° C. ¹HNMR (CD₃OD/300 MHz) 7.77 (d, 1H, J=2.2 Hz), 7.71 (s, 1H), 7.41 (d, 1H,J=2.2 Hz), 5.87 (q, 1H, J=7.0 Hz). EIHRMS m/z 403.8893 (M−H, Calc'd.403.8924). Anal. Calc'd for C₁₁H₅ClF₃IO₃: C, 32.66; H, 1.25. Found: C,33.13; H, 1.29.

EXAMPLE 74

[1022]

[1023] 8-Bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[1024] Step 1. Preparation of ethyl8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

[1025] A mixture of 3-bromo-5-chlorosalicylaldehyde (1.9 g, 4.2 mmol),potassium carbonate (0.58 g, 4.2 mmol), and ethyl4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) was stirred inN,N-dimethylformamide (5 mL) at 95° C. for 18 h. Water (100 mL) wasadded and the mixture was extracted with ether (3×50 mL). The combinedorganic extracts were washed with sodium hydroxide (10 mL) and water(2×50 mL). After drying over MgSO₄ and concentrating, the mixturefiltered through of a pad of silica eluting with ethyl acetate-hexanes(1:4). The eluant was concentrated and a light yellow solid wascrystallized from cold hexane (0.43 g, 26%): mp 101.0-102.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.65 (d, H, J=2.4 Hz), 7.61 (d, H,J=2.4 Hz), 6.03 (q_(H-F), 1H, J=6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H, J7.5 Hz). ESHRMS m/z 384.9435 (M−H, Calc'd 384.9454). Anal. Calc'd forC₁₃H₉BrClF₃O₃: C, 40.50; H, 2.35. Found: C, 40.61; H, 2.40.

[1026] Step 2. Preparation of8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyra -3-carboxylic acid

[1027] Ethyl8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-caboxylate (0.3 g),ethanol (15 mL), tetrahydrofuran (10 mL), and sodium hydroxide solution(10 mL, 2.5 N) were stirred at room temperature for 16 h. Hydrochloricacid (1 N) was added until the mixture was acidic to pH paper. Theaddition of water (50 mL) caused the formation of a precipitate whichwas collected by filtration yielding the title compound as a white solid(0.2 g, 72%): mp 227.8-228.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s,1H), 7.65 (dd, 2H, J=2.4 and J=28.8 Hz), 6.00 (q_(H-F), 1H, J=7.2 Hz).FABHRMS m/z 356.9134 (M+H, Calc'd 356.9141). Anal. Calc'd forC₁₁H₅BrClF₃O₃: C, 36.96; H, 37.05; H, 1.33.

EXAMPLE 75

[1028]

[1029] 6-Formyl-2-(trifluoromethyl)-25-1-benzopyran-3-carboxylic acid

[1030] Step 1. Preparation of ethyl6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1031] A 50 mL round bottom flask was charged with5-formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol),dimethylformamide (15 mL) and potassium carbonate (2.95 g, 21.39 mmol)and heated to 60° C. for 12 hours. Additional ethyl4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and thereaction heated for 16 hours at 75° C. After cooling to roomtemperature, the reaction was partitioned between H₂O and diethyl ether.The organic phase was washed with saturated NaHCO₃ solution, KHSO₄solution (0.25 M), brine, treated with decolorizing carbon (warmedgently). The resulting black suspension was dried over MgSO₄, vacuumfiltered through diat s earth, and concentrated in vacuo yielding anolange crystalline mass. This material was recrystallized from hothexanes yielding the ester (1.51 g, 24%) as orange crystals: mp84.3-86.2° C. ¹H NMR (acetone-d₆/300 MHz) 9.96 (s, 1H), 8.06 (d, 1H,J=2Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J=8.5, 2.0Hz), 7.24 (d, 1H, J=8.5Hz), 5.99 (q, 1H, J=7.1 Hz), 4.43−4.25 (m, 2H), 1.34 (t, 3H, J=7.3 Hz).FABLRMS m/z 301 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal.Calc'd for C₁₄H₁₁F₃O₄: C, 56.01; H, 3.69. Found: C, 56.11; H, 3.73.

[1032] Step 2. Preparation of6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1033] The ester (Step 1) was converted to the acid via a method similarto that described in Example 1, Step 2: mp 211.3-215.7° C. ¹H NMR(acetone-d₆/300 MHz) 9.97 (s, 1H), 8.07 (d, 1H, J=2.0 Hz), 8.03 (s, 1H),8.00 (dd, 1H, J=8.3, 2.0 Hz), 7.25 (d, 1H, J=8.5 Hz), 5.98 (q, 1H, J=6.9Hz). FABLRMS m/z 273 (M+H). EIHRMS m/z 272.0266 (M+, Calc'd 272.0296).Anal. Calc'd for C₁₂H₇F₃O₄: C, 52.95; H, 2.59. Found: C, 52.62; H, 2.58.

EXAMPLE 76

[1034]

[1035]6-Chloro-8-Formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1036] Step 1. Preparation of 4-chloro-2,6-bis(hydroxymethyl)phenol.

[1037] Potassium hydroxide (84.82 g, 1.30 mole) was dissolved in H₂O(200 mL) in a two liter 3-neck round bottom flask fitted withthermocouple, mechanical stirrer, and stopper. With stirring,4-chlorophenol (128.56 g, 1.0 mole) was added with cooling (ice bath)resulting in the temperature rising to 26° C. Formalin (230 mL of 37%aqueous solution, 2.83 mole) was added portion-wise maintaining thetemperature below 25° C. The reaction was warmed to 35° C. for 48 hours.To this solution was added aqueous acetic acid (80.0 mL, 84.1 g, 1.40mole in 800 mL H₂O) causing the solution to become turbid. Vacuumfiltration of the suspension yielded a tan solid. The solid was stirredwith acetone (100 mL) and the insoluble product collected by vacuumfiltration. The solution was diluted with hexanes yielding several cropsof the diol as fine tan needles (35.0 g, 19%). mp 160.6-163.3° C. ¹H NMR(acetone-d₆, NaOD, D₂O/300 MHz) 6.69 (s, 2H), 4.48 (s, 4H), 7.88 (d, 1H,J=2.6 Hz), 7.75 (d, 1H, J=2.6 Hz), 6.08 (q, 1H, J=6.9 Hz). ESLRMS m/z206 (M+NH₄ ⁺). ESHRMS m/z 187.0131 (M−H, Calc'd 187.0162).

[1038] Step 2. Preparation of 5-armyl-salicylaldehyde.

[1039] To a stirred suspension of diol (Step 1) (33.0 g, 0.18 mole) inchloroform (1.5 L) in a 2 L round bottom flask was added manganesedioxide (139 g, 1.60 mole) and the resulting suspension heated to agentle reflux for 10 hours. The reaction was allowed to cool to roomtemperature, was filtered through diatomaceous earth, concentrated invacuo, presorbed on silica gel and purified by flash chromatography(hexane/ethyl acetate) yielding the as a mustard colored powderdialdehyde (22.42 g, 67%): mp 120.7-122.8° C. This solid was of suitablepurity to use in the next step without further purification.

[1040] Step 3. Preparation of ethyl6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1041] A stirred solution of the dialdehyde (Step 2) (1.13 g, 6.14mmol), dimethyl sulfoxide (6 mL), ethyl 4,4,4-trifluorocrotonate (1.37mL, 1.55 g, 9.21 mmoL) and triethylamine (1.71 mL, 1.24g, 12.28 mmol) ina round bottom flask fitted with condenser was heated to 80° C. for 8 h.Upon cooling to room temperature the reaction was diluted with diethylether (100 mL) and the resulting mixture washed with aqueous sodiumbicarbonate solution (3×75 mL), 1 N HCl solution (3×70 mL), and brine(1×75 mL), dried over MgSO₄, filtered and concentrated in vacuo yieldinga tan powder. This powder was taken up in hot hexane-ethyl acetate andfiltered to remove insoluble matter. Upon cooling of the filtrate,crystallization followed by vacuum filtration yielded the desired esteras tan crystals (0.726 g, 35%): mp 118.1-119.7° C. This material was ofsuitable purity to use without purification.

[1042] Step 4. Preparation of6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1043] To a stirred solution of the ester (Step 3)(0.284 g, 0.849 mmol)in THF:EtOH:H₂O (7:2:1, 5 mL) was added aqueous NaOH solution (0.41 mLof 2.5 M, 1.02 mmol). After stirring 40 hours, the reaction waspartially concentrated in vacuo to remove the organic solvents, dilutedwith H₂O, washed with diethyl ether, sparged with nitrogen to removetrace diethyl ether, and acidified with concentrated HCl yielding asuspension. Vacuum filtration of the suspension yielded the titlecompound as a pale yellow powder (0.160 g, 23%) mp 243.3-252.4° C. ¹HNMR (acetone-d₆/300 MHz) 10.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H, J=2.6Hz), 7.75 (d, 1H, J=2.6 Hz), 6.08 (q, 1H, J=6.9 Hz). FABLRMS m/z 307(M+H). ESHRMS m/z 304.9839 (M−H, Calc'd 304.9828). Anal. Calc'd forC₁₂H₆Cl₁F₃O₄: C, 47.01; H, 1.97. Found: C, 46.64; H,1.86.

EXAMPLE 77

[1044]

[1045]6-Bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1046]7-(1,1-Dimethylethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid (Example 12)(0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01g, 0.2 mmol), and bromine (0.48 g, 3.00 mmol) were stirred at reflux for16 h. The mixture was allowed to cool and was washed with brine (2×50mL). After drying over MgSO₄, the mixture was filtered, concentrated invacuo, and the residue crystallized from ether-hexanes yielding thetitle compound as a white solid (0.5 g, 66%): mp 198.6-199.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.83 (q,1H, J=7.2 Hz), 1.5 (s, 9H). Anal. Calc'd for C₁₅H₁₄O₃F₃Br: C, 47.52; H,3.72; N, 21.07. Found: C, 47.42; H, 3.68; N, 21.15.

EXAMPLE 78

[1047]

[1048] 5,6-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1049] 5,6-Dichlorosalicylaldehyde was prepared by the proceduredescribed in Cragoe, E. J.; Schultz, E. M., U.S. Pat. No. 3,794,734,1974. This salicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 1: mp 211.5-213.5° C. ¹HNMR (acetone-d₆/300 MHz) 8.09 (s, 1H), 7.63 (d, 1H, J=8.9 Hz), 7.12 (d,1H, J=8.9 Hz), 5.94 (q, 1H, J=7.0 Hz). ESLRMS m/z 311 (M−H). EIHRMS m/z311.9583 (M+, Calc'd 311.9568). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20;H, 1.61. Found: C, 42.33; H, 1.67.

EXAMPLE 79

[1050]

[1051] 6-Cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1052] Step 1. Preparation of ethyl6-[(hydroxyimino)methyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1053] A 50 mL round bottom flask was charged with hydroxylamine HCl(0.255 g, 3.67 mmol), ethyl6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 75,Step 1) (1.00 g, 3.34 mmol), sodium acetate (0.301 g, 3.67 mmol),ethanol (10 mL), and H₂O (2 mL). The reaction was stirred at roomtemperature for 18 hours, then diluted with H₂O and diethyl ether. The lrated and the organic phase wash brine, dried over MgSO₄, filtered, andconcentrated in vacuo yielding an orange semi-crystalline mass.Recrystallization of this solid from hot ethyl acetate and isooctaneyielded the oxime (0.578 g, 55%): mp 113.0-116.2° C. ¹H NMR(acetone-d₆/300 MHz) 10.46 (s, ca.1 exch.), 8.11 (s, 2H), 7.92 (s, 1H),7.72 (d, 1H, J=2Hz)), 7.68 (dd, 1H, J=8.5, 2.0 Hz), 7.07 (d, 1H, J=8.5Hz), 5.89 (q, 1H, J=7.1 Hz), 4.43−4.22 (m, 2H), 1.34 9t, 3H, J=7.3 Hz).FABLRMS m/z 316 (M+H). EIHRMS m/z 315.0719 (M+, Calc'd 315.0733). Anal.Calc'd for C₁₄H₁₂F₃N₁O₄: C, 53.34; H, 3.84; N 4.44. Found: C, 53.85; H,3.90; N, 4.19.

[1054] Step 2. Preparation of ethyl6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1055] To a stirred solution of oxime (Step 1)(0.264 g, 0.840 mmol) indioxane (4.5 mL) in a 25 mL pear-shaped flask was added trifluoroaceticanhydride (0.130 mL, 0.194 g, 0.924 mmol) and triethylamine (0.140 mL,0.102 g, 1.008 mmol). The reaction was stirred at room temperature for12 hours, then heated to 85° C. for 4 hours. After cooling to roomtemperature, aqueous HCR (50 ml, 1 N HCL) was added, and the resultingmixture extracted with ethyl acetate. The ethyl acetate phase was washedwith chilled aqueous HCl (1 N), brine, dried over Na₂SO₄, filtered,concentrated in vacuo yielding a pale yellow oil. This oil wasresubmitted to similar reaction conditions. After dissolution of thepale yellow oil in dioxane (4.5 mL), tracetic anhydride (0.130 mL, 0.194g, 0.924 mmol) and triethylamine (0.140 mL, 0.102 g, 1.008 mmol) werethen added. After stirring 3 hours at room temperature, moretriethylamine 0.50 mL, 0.36 g, 3.6 mmol) was added and then heated to85° C. for 3 hours. After cooling to room temperature, aqueous HCl (50ml, 1 N HCL) was added, and the resulting mixture extracted with ethylacetate. The ethyl acetate phase was washed with chilled aqueous HCl (1N), brine, dried over Na₂SO₄, filtered, concentrated in vacuo yielding apale yellow oil. Addition of hexanes induced crystallization followed byvacuum filtration yielded the title compound (0.101 g, 40%) as a yellowpowder: mp 101.6-106.1° C. ¹H NMR (acetone-d₆/300 MHz) 7.97 (d, 1H,J=2.2 Hz), 7.95 (s, 1H), 7.82 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H,J=8.5 Hz), 6.01 (q, 1H, J=7.1 Hz), 4.38−4.24 (m, 2H), 1.34 (t, 3H, J=7.3Hz). FABLRMS m/z 298 (M+H). EIHRMS m/z 297.0575 (M+, Calc'd 297.0613).

[1056] Step 3. Preparation of6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1057] To a stirred solution of the ester (Step 2)(0.077 g, 0.259 mmol)in THF-EtOH-H₂O (7:2:1, 2 mL) in a 5 mL pear-shaped flask was addedaqueous NaOH (0.13 mL, 2.5 N solution) in one portion. After stirringfor 6 hours at room temperature the solution was partially concentratedin vacuo to remove most of the THF and EtOH. The resulting solution wasdiluted with H₂O and washed with diethyl ether. The resulting aqueousphase was sparged with nitrogen to remove trace diethyl ether and wasacidified with concentrated HCl yielding a sticky suspension. Thesuspension was extracted with diethyl ether and the ether was dried overMgSO₄, filtered and concentrated in vacuo yielding a pale yellow oil.This oil was crystallized from methylene chloride-hexanes yielding thetitle compound (0.041 g, 59%) as a tan powder: mp 185.1-186.1° C. ¹H NMR(acetone-d₆/300 MHz) 7.99−7.94 (m, 2H), 7.83 (dd, 1H, J=8.5, 2.0 Hz),7.25 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.0 Hz). FABLRMS m/z 270 (M+H).EIHRMS m/z 269.0316 (M+, Calc'd 269.0300).

EXAMPLE 80

[1058]

[1059] 6-Hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1060] To a chilled (ice bath), stirred solution of6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example75, Step 2) (0.133 g, 0.489 mmol) in THF (1 mL) and ethanol (1 mL) in a10 mL round bottom flask was added NaBH, (0.020 g, 0.528 mmol) in twoportions. The reaction was allowed to warm to room temperature and moreNaBH₄ (0.050 g, 1.322 mmol) was added. The total reaction time was 3hours. The reaction was quenched with aqueous HCl (1 N solution) and wasextracted with chloroform. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo yielding a foam. This crude productwas purified by flash chromatography (silica gel 60, eluant 1:1,hexane-ethyl Acetate with 2% acetic acid). The product collected fromthe chromatography was recrystallized from hexanes and ethyl acetate,and collected by vacuum filtration yielding the title compound (0.042 g,31%) as a very pale yellow powder: mp 177.5-180.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz),6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMSm/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'dfor C₁₂H₉F₃O₄: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.

EXAMPLE 81

[1061]

[1062]6-(Difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1063] Step 1. Preparation of ethyl6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzo late.

[1064] Ethyl 6-formyl-2-trif- 1-benzopyran-3-carboxylate (Example 75,Step 1)(1.672 g, 5.569 mmol) in methylene chloride (1.5 mL) was added tomethylene chloride (1.5 mL) and diethylaminosulfur trifluoride (DAST)(0.74 mL, 0.898 g, 5.569 mmol) over 0.07 hours via syringe. Afterstirring for 20 hours the reaction was poured into aqueous HCl (2.0 N)and the mixture was extracted with diethyl ether. The ethereal phase waswashed with dilute aqueous HCl (2.0 N), saturated NaHCO₃ solution,brine, dried over MgSO₄, filtered and concentrated in vacuo yielding aclear colorless oil. This oil was purified by flash chromatography(Silica gel 60, Eluant (5:1; Hexanes Ethyl Acetate) yielding ethyl6-difluoromethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (0.96g, 54%) as an oil which solidified upon standing. This product was ofsufficient purity to be used in the next step without furtherpurification: ¹H NMR (acetone-d₆/300 MHz) 7.97 (s, 1H), 7.74 (s, 1H),7.65 (d, 1H, J=8.5 Hz), 7.18 (d, 1H, J=8.5 Hz), 6.90 (t, 1H, J=56.0 Hz),5.94 (q, 1H, J=7.0 Hz), 4.40−4.25 (m, 2H), 1.34 (t, 3H, J 7.0 Hz).

[1065] Step 2. Preparation of6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1066] Aqueous NaOH (1.31 mL, 3.277 mmol, 2.5 M solution) was added inone portion to the ester (Step 1) (0.880 g, 2.731 mmol) in THF:EtOH:H₂O(7:2:1, 10 mL). The resulting solution was stirred for 60 hours. Thereaction mixture was partially concentrated in vacuo to remove theorganic solvents and was diluted with H₂O. The resulting aqueoussolution was washed with diethyl ether, sparged with nitrogen to removetrace ether, and actied with concentrated HCl. The resulting ofsuspension was extracted with diethyl ether. The combined organic phaseswere dried over MgSO₄, filtered and concentrated in vacuo yielding thetitle compound (0.483 g, 60%) as an oil which solidified as a whitecrystalline mass: mp 134.7-136.2° C. ¹H NMR (acetone-d₆/300 MHz) 7.97(s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=8.5, 1.0 Hz), 7.17 (d, 1H, J=8.5Hz), 6.89( t, 1H, J=56.2 Hz), 5.90 (q, 1H, J=7.1 Hz). FAB-ESLRMS m/z 293(M−H). EIHRMS m/z 293.0235 (M−H, Calc'd 293.0237). Anal. Calc'd forC₁₂H₇F₅O₃: C, 49.00; H, 2.40. Found: C, 48.78; H,2.21.

EXAMPLE 82

[1067]

[1068] 2,6-Bia(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1069] Step 1. Preparation of Ethyl2,6-bis(trifluoromethyl)-4-oxo-4H-1-benzopyran-3-carboxylate.

[1070] To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wisesodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol)causing gas evolution. After gas evolution has subsided,2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) wasadded. The reaction was stirred at room temperature for 24 hours, thenheated to 105° C. for 24 hours. After cooling to room temperature, thereaction was diluted with diethyl ether and the resulting solution waswashed with H₂O and brine, dried over MgSO₄, filtered and concentratedin vacuo yielding a slightly sticky white solid. This solid wastriturated with hexanes yielding the desired ester(3.05 g, 39%) as awhite powder: mp 116-120.1° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (d, 2H, J=1.6Hz), 8.03 (dd, 1H J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H,J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'dfor C₁₄H₈F₆O₄: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.

[1071] Step 2. Preparation of ethyl2,6-bis(trifluoromethyl)-4-oxo-dihydrobenzopyran-3-carboxylate.

[1072] A 250 mL round both urged with ethyl2,6-bis(trifluoromethyl)-benzopyran-4-one-3-carboxylate (Step 1)(2.307g, 6.513 mmol) and THF (20 mL) yielding a pale yellow solution. Ethanol(20 mL) was added and the reaction chilled in an ice-salt bath. Whilemaintaining the reaction temperature at below 9° C., NaBH₄ (0.246 g,6.513 mmol) was added in two portions and the mixture stirred 1 h. Thecrude reaction mixture was poured into a vigorously stirred mixture ofice (200 mL) and concentrated HCl (12 N, 5 mL) yielding a precipitate.Vacuum filtration of the resulting suspension yielded the desired ketoester (2.204 g, 87%) as faint pink powder of suitable purity to use inthe next step without further purification: mp 71.8-76.9° C. ¹H NMR(acetone-d₆/300 MHz) 12.71 (br s, 1H exch), 8.01 (d, 1H, J=2.0 Hz), 8.01(d, 1H, J=2.0 Hz), 7.88 (dd, 1H, J=8.7, 1.8 Hz), 7.31 (d, 1H, J=8.7 Hz),5.98 (q, 1H, J=6.6 Hz), 4.51−4.28 (m, 2H), 1.35 (t, 3H, J=7.0 Hz).FABLRMS m/z 355 (M−H). ESHRMS m/z 355.0394 (M−H, Calc'd 355.0405).

[1073] Anal. Calc'd for C₁₄H₁₀F₆O₄: C, 47.21; H., 2.83. Found: C, 47.31;H,2.97.

[1074] Step 3. Preparation of ethyl2,6-bis(trifluoromethyl)-4-trifluoromethanesulfonate-2H-1-benzopyran-3-carboxylate.

[1075] A 50 mL 3-neck Morton flask fitted with addition funnel, 2stoppers was charged with 2.6-di-tert-butylpyridine (1.576 methylenechloride (12 mL), and then via syringe was addedtrifluoromethanesulfonic anhydride (1.08 mL, 1.80 g, 1.25 mmol). To thissolution was added dropwise a solution the keto ester (Step 2) (1.822 g,5.115 mmol) in methylene chloride (10 mL) over 0.33 h and the reactionstirred for 48 h. The resulting off-white suspension was transferred toa 100 mL round bottom flask and was concentrated in vacuo. The residuewas suspended in diethyl ether (50 mL) and vacuum filtered to removesalts. The filtrate was further diluted with diethyl ether (50 mL) andwas washed with ice cold HCl solution (2 N), brine, and dried overNa₂CO₃, filtered and concentrated in vacuo yielding the desired triflate(1.64 g, 66%) as a tan clumpy powder of suitable purity to use in thenext step without further purification.

[1076] Step 4. Preparation of ethyl2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1077] A 25 mL pear flask was charged with LiCl (0.136 g, 3.219 mmol),affixed to a high vacuum line and heated with a heat gun removingsuperficial water. The flask was allowed to cool to room temperature,and tetrakis(triphenylphosphine)palladium(0)(0.124 g, 0.107 mmol) andTHF (2 mL) were added. A reflux condenser was affixed to the flask andthe apparatus was purged with nitrogen. A solution of the triflate(Step3)(0.524 g, 1.073 mmol)in THF (2 mL) and tri-n-butyltin hydride (0.32mL, 0.34 g, 1.18 mmol) were added sequentially via syringe. Theresulting light orange solution was heated to 50° C. with stirring for 1h, 60° C. for one hour, and 65° C. for one hour. The reaction wasallowed to cool to room temperature and was poured into 2 N HCl,stirred, and extracted with hexanes. The hexane phase was dried overMgSO₄, filtered and concentrated yielding a light br The oil wasdissolved in hexane and was washed with aqueous ammonium fluoridesolution. The resulting hexane phase was dried over MgSO₄, filtered andconcentrated in vacuo yielding a dull yellow oily solid which solidifiedas a flaky powder (0.443 g). This solid was purified by flash silicachromatography (eluant: hexanes-methylene chloride, 4:1) yielding ethyl2,6-di-trifluoromethyl-2H-1-benzopyran-3-carboxylate(0.069 g, 19%) as awhite crystalline solid of suitable purity to proceed with the nextstep.

[1078] Step 5. Preparation of2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1079] To a stirred solution of the ester (Step 4) (0.065 g, 0.191 mmol)in THF-EtOH-H₂O (7:2:1, 1 mL) was added NaOH solution (0.084 mL, 0.210mmol)in one portion at room temperature and allowed to stir overnight.The reaction was partially concentrated in vacuo yielding a pale yellowclear syrup. The syrup was diluted with water (5 mL) and brine (1 mL)and was washed with diethyl ether (3×5 mL). The resulting aqueous phasewas sparged with nitrogen to remove trace ether. With stirring,concentrated HCl was added to the aqueous phase causing the formation ofa very fine white precipitate. This suspension was extracted withdiethyl ether and the ether dried over Na₂SO₄, filtered, andconcentrated by slow evaporation at atmospheric pressure. The resultingproduct was recrystallized from hexanes and ethyl acetate yielding thetitle compound (0.038 g, 64%) as a fine tan powder: mp 143.5-145.2° C.¹H NMR (acetone-d₆/300 MHz) 11.97−11.67 (br s, 1H), 8.03 (s, 1H), 7.92(s, 1H), 7.77 (d, 1H, J=8.5 Hz), 7.26 (d, 1H, J=8.7 Hz), 5.96 (q, 1H,J=7.0 Hz). FABLRMS m/z 311 (M−H). ESHRMS m/z 311.0107 (M−H, Calc'd311.0143).

EXAMPLE 83

[1080]

[1081] 5,6,7-Trichloro-2-(trifluoromethyl)-2N-1-benzopyran-3-carboxylicacid

[1082] 3,4,5-Trichlorophenol was converted to 3-ethoxysalicylaldehydevia a procedure similar to that described in Example 11, Step 1. The4,5,6-trichlrorsalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 236.2-239.3° C. ¹HNMR (acetone-d₆/300 MHz) 8.05 (s, 1H), 7.40 (s, 1H), 5.99 (q, 1H, J=7.0Hz). ESLRMS m/z 345 (M−H). ESHRMS m/z 344.9113 (M−H, Calc'd 344.9100).Anal. Calc'd for C₁₁H₄Cl₃F₃O₃+0.89 wt % H₂C: 37.68; H, 1.25; Cl, 30.33.Found: C, 37.48; H,1.2 0.33.

EXAMPLE 84

[1083]

[1084] 6,7,8-Trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1085] 2,3,4-Trichlorophenol was converted to 3-ethoxysalicylaldehydevia a procedure similar to that described in Example 11, Step 1. The3,4,5-trichlrorsalicyladehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 222.0-225.3° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.78 (s, 1H), 6.07 (q, 1H, J=7.0Hz). ESLRMS m/z 345 (M−H). EIHRMS m/z 344.9117 (M−H, Calc'd 344.9100).Anal. Calc'd for C₁₁H₄Cl₃F₃O₃+1.56 wt % H₂O: C, 37.43; H, 1.32; Cl,30.13. Found: C, 37.79; H,0.93; Cl, 29.55.

EXAMPLE 85

[1086]

[1087] 7-Ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[1088] 3-Ethylphenol was converted to the title compound by a proceduresimilar to that described in Example 2. : mp 167.0-168.6° C. ¹H NMR(CDCl₃/300 MHz) 7.84 (s, 1H), 7.15 (d, 1H, J=7.5 Hz), 6.84 (m, 2H), 5.66(q, 1H, J=6.8 Hz), 2.63 (q, 2H, J=7.7 Hz, J=7.7 Hz), 1.24 (t, 3H, J=7.7Hz). Anal. Calc'd for C₁₃H₁₁F₃O₃: C, 57.36; H, 4.07. Found: C, 57.25; H,4.10.

EXAMPLE 86

[1089]

[1090]6-(Methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1091] Step 1. Preparation of ethyl6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1092] Ethyl6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 2, Step 2) (1.014 g, 3.18 mmol) in methylene chloride waschilled to −50° C. (dry ice acetone). With stirring,meta-chloroperbenzoic acid (0.91 g of 60% reagent, 3.18 mmol) was addedand reaction allowed to proceed for 3 hours. Aqueous NaHSO₃ solution (40mL 0.25 M) was poured into the reaction. More methylene chloride wasadded and the layers mixed, then separated. The organic phase was washedwith aqueous NaHSO₃ solution, aqueous saturated NaHCO₃ solution, brine,dried over MgSO₄, filtered and concentrated yielding an oil. The oil wasdiluted with isooctane (2 mL) and concentrated yielding an oil whichupon standing crystallized. Hexanes was added, the solution was heated,and methylene chloride added until partial dissolution occurred. Aftercooling and standing overnight the suspension was vacuum filteredyielding the sulfoxide substituted ethyl ester (0.753 g, 71%) as whiteneedles: mp 92.2-98.4° C. This ester was of sufficient purity to be usedwithout further purification.

[1093] Step 2. Preparation of6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1094] To a stirred solution of the ester (Step 1) (0.683 g, 2.043 mmol)in THF:EtOH:H₂O (7:2:1, 4 mL) was added aqueous NaOH solution (0.98 mLof 2.5 M, 2.45 mmol). After stirring 12 hours, the reaction waspartially concentrated in vacuo to remove the organic solvents. Theresidue was diluted with H₂O, washed with diethyl ether, sparged withnitrogen to remove trace diethyl ether, and acidified with concentratedHCl yielding a oily suspension. The suspension was extracted withdiethyl ether, and the resulting organic phase dried over MgSO4,filtered, and diluted with hexanes. Upon concentration in vacuo thetitle acid was obtained as a sticky white powder(0.425 g, 68%): mp148.3-151.0° C. ¹H NMR (acetone-d₆/300 MHz) 7.99 (s, 1H), 7.82 (s, 1H),7.78−7.68 (m, 1H), 7.24 (d, 1H, J=8.3 Hz), 5.92 (q, 1H, J=7.1 Hz), 2.73(s, 3H). FABLRMS m/z 307 (M+H). ESHRMS m/z 305.0098 (M−H, Calc'd305.0095). Anal. Calc'd for C₁₂H₉F₃O₄S₁: C, 47.06; H, 2.96; S, 10.47.Found: C, 46.69; H,2.86; S, 10.45.

EXAMPLE 87

[1095]

[1096] 5,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1097] 2,5-Dichlorophenol was converted to 3,6-dichlorosalicylaldehydevia a procedure similar to that described in Example 2, Step 1. The3,6-dichlorosalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp205.7-207.1° C. ¹H NMR (acetone-d₆/300 MHz) 8.02 (s, 1H), 7.53 (d, 1H,J=8.7 Hz), 7.22 (d, 1H, J=8.7 Hz), 6.04 (q, 1H, J=7.1 Hz). FABLRMS m/z311 (M−H). ESHRMS m/z 310.9506 (M−H, Calc'd 310.9490). Anal. Calc'd forC₁₁H₅Cl₂F₃O₃+0.63 wt % H₂O: C, 41.94; H, 1.67. Found: C, 41.54; H,1.27.

EXAMPLE 88

[1098]

[1099]6-(Pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1100] Step 1. Preparation of ethyl6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1101] Potassium pentafluoropropionate (0.476 g, 2.35 mmol) wasdissolved in toluene (6 mL) and DMF (6 mL). The vessel was fitted with adistilling head, and CuI (0.471 g, 2.474 mmol) was added with stirring.The reaction was heated to 120° C., removing the toluene bydistillation. Ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72,Step 3)(0.469 g, 1.178 mmol) was added and the reaction was heated to150° C. for 2 hours. The reaction was allowed to cool to roomtemperature and was partitioned between diethyl ether and H₂O. Theorganic phase was dried over MgSO₄, filtered and concentrated in vacuo.The resulting residue was purified by flash chromatography (silica gel60, eluant: hexanes-ethyl acetate, 8:1) yielding, upon concentration ofthe solution, the desired ester (0.096 g, 21%) as a tan solid mass ofsuitable purity to use without further purification: ¹H NMR(acetone-d₆/300 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H,J=8.7, 2.2 Hz), 6.00 (q, 1H, J=7.1 Hz), 4.42−4.24 (m, 2H), 1.34 (t, 3H,J=7.3 Hz).

[1102] Step 2. Preparation of6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1103] To a stirred solution of the ethyl ester (Step 1)(0.090 g, 0.231mmol) in THF:EtOH:H₂0(7:2:1) (4 mL) was added aqueous NaOH solution(0.11 mL, 2.5 M). After stirring 16 hours, the reaction was partiallyconcentrated in vacuo to remove the organic solvents, diluted with H₂O,and washed with diethyl ether. The resulting aqueous phase was acidifiedwith concentrated HCl, extracted with diethyl ether, dried over MgSO₄,filtered and concentrated in vacuo yielding an oil. The oil was purifiedby flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5%acetic acid). This procedure yielded the title acid (0.020 g, 24%) as awhite p mp 162.3-164.7° C. ¹H NMR (acet ₆/300 MHz) 8.05 (s, 1H), 7.90(s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97 (q, 1H,J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H, Calc'd361.0094).

EXAMPLE 89

[1104]

[1105]6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1106] 4-tert-Butylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 170.6-173.2° C. ¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.5−7.4 (m, 2H), 6.93 (d, 1H,J=8.4 Hz), 5.76 (q, 1H, J=7.2 Hz), 1.3 (s, 9H). Anal. Calc'd forC₁₅H₁₅O₃F₃: C, 60.00; H, 5.04. Found: C, 59.93; H, 5.12.

EXAMPLE 90

[1107]

[1108]5-(Hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylicacid

[1109] 3-Hydroxylmethyl-5-methyl-4-formylpyridine was converted to thetitle compound by a procedure similar to that described in Example 1: mp76.1-80.1° C. ¹H NMR (acetone-d₆/300 MHz) 8.15 (s, 2H), 5.93 (q, 1H,J=7.2 Hz), 1.3 (s, 9H) 5.30 (br s, 1H) 4.79 (br s, 1H), 2.41 (s, 3H).ESHRMS m/z 288.0485 (M+H, Calc'd 288.0483).

EXAMPLE 91

[1110]

[1111]2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylicacid

[1112] 4-(Trifluoromethoxy)phenol was converted to5-(trifluoromethoxy)salicylaldehyde via a procedure similar to thatdescribed in Example 2, Step 1. The 5-(trifluoromethoxy)salicylaldehydewas converted to the title compound by a similar procedure to thatdescribed in Example 11, Steps 2 & 3: mp 139.1-143.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.95 (s, 1H), 7.88 (d, 2H, J=2.4 Hz), 7.71−7.75 (m,1H), 6.93 (d, 1H, J=8.7 Hz), 5.91 (q, 1H, J=6.9 Hz). Anal. Calc'd forC₁₂H₆O₃F₃S: C, 41.87; H, 1.76. Found: C, 41.94; H, 1.84.

EXAMPLE 92

[1113]

[1114] 6-(Trifluoromethyl)-6H- xolo[4,5-g][1]benzopyran-7-carboxylicacid

[1115] 4-tert-Butylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 245.8-247.8° C. ¹HNMR (acetone-d₆/300 MHz) 7.77 (s, 1H), 6.95 (s, 1H), 6.12 (s, 1H), 6.05(d, 2H, J=0.90 Hz), 5.91 (q, 1H, J=7.2 Hz). Anal. Calc'd for C₁₂H₇O₅F₃:C, 50.01; H, 2.45. Found: C, 50.02; H, 2.50.

EXAMPLE 93

[1116]

[1117] 8-Ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

[1118] 2-Ethoxyphenol was converted to 3-ethoxysalicylaldehyde via aprocedure similar to that described in Example 11, Step 1. The3-ethoxysalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 159.4-160.9° C. 1HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 6.97-7.14 (m, 3H), 5.83 (q_(H-F),1H, J=7.2 Hz), 4.12 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz). FABHRMSm/z 289.0656 (M+H, Calc'd 289.0686). Anal. Calc'd for C₁₃H₁₁F₃O₄: C,54.17; H, 3.85. Found: C, 54.06; H. 3.83.

EXAMPLE

[1119]

[1120] 6-Chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1121] 4-Chloro-3-(trifluoromethyl)phenol was converted to the titlecompound by a procedure similar to that described in Example 11: mp180.9-182.4° C. ¹H NMR (acetone-d6/300 MHz) 7.96 (s, 1H), 7.84 (s, 1H),7.47 (s, 1H), 5.96 (q, 1H, J=6.8 Hz), 2.50 (s, 3H). FABLRMS m/z 345(M−H). FABHRMS m/z 344.9767 (M−H, Calc'd 344.9753). Anal. Calc'd forC₁₂H₅ClF₆O₃: C, 41.58; H, 1.45; Cl, 10.23. Found: C, 41.57; H, 1.50; Cl,10.33.

EXAMPLE 95

[1122]

[1123] 5-Methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1124] 6-Methoxysalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp204.5-206.7° C. ¹H NMR (acetone-d₆/300 MHz) 8.08 (s, 1H), 7.38 (dd, 1H,J=8.5 Hz 8.3 Hz), 6.74 (d, 1H, J=8.5 Hz), 6.65 (d, 1H, J=8.3 Hz), 5.80(q, 1H, J=7.2 Hz), 3.94 (s, 3H). FABLRMS m/z 273 (M−H). EIHRMS m/z274.0444 (M+, Calc'd 274.0453). Anal. Calc'd for C₁₂H₉F₃O₄: C, 52.57; H,3.31. Found: C, 52.47; H, 3.34.

EXAMPLE 96

[1125]

[1126] 6-Benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1127] Step 1. Preparation of ethyl6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1128] Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example10, Step 1)(1.59 g, 5.8 mmol) was dissolved in 1,2-dichloroethane (3 mL)and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol)in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g,7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction washeated to 80° C. and stirred for 4 hours. The solution was poured onto 3N HCl and ice and extracted with ethyl acetate. The ethyl acetate layerswere combined, washed with 3N HCl, saturated sodium bicarbonate, brine,dried over MgSO₄ and concentrated in vacuo. The crude ester was purifiedby flash chromatography over silica gel (with 1:9 ethyl acetate/hexaneas eluant) to afford the ester as a white crystalline solid (0.26 g,12%): mp 114.7-116.1° C. ¹H NMR (CDCl₃/300 MHz) 7.82 (dd, 1H, J=8.5 Hz2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).

[1129] Step 2. Preparation of6-benzoyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[1130] The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2mL) and ethanol (2 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8mmol), and stirred at room temperature for 4.3 hours. The reactionmixture was concentrated in vacuo, acidified with 3N HCl yielding asolid. The solid was collected by filtration and was recrystallized fromethanol-water to yield a white 64%): mp 269.8-270.8° C. ¹H NMR(acetone-d₆/300 MHz) 8.04 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.88 (dd, 1H,J=8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.23 (d, 1H,J=8.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 347 (M−H). ESHRMS m/z347.0560 (M−H, Calc'd 347.0531). Anal. Calc'd for C₁₈H₁₁F₃O₄: C, 62.08;H, 3.18. Found: C, 61.48; H, 3.22.

EXAMPLE 97

[1131]

[1132]6-(4-Chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1133] The 2H-1-benzopyran-3-carboxylic acid was prepared analogous tothe procedure described in Example 96: mp 268.3-269.4° C. ¹H NMR(acetone-d₆/300 MHz) 8.03 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.89 (dd, 1H,Hz, 2.0 Hz), 7.81 (d, 2H, J=8.5 Hz , J=8.5 Hz), 7.23 (d, 1H, J=8.5 Hz),5.q, 1H, J=7.1 Hz). FABLRMS m/z 381 (M−H). ESHRMS m/z 381.0135 (M−H,Calc'd 381.0141). Anal. Calc'd for C₁₈H₁₀ClF₃O₄: C, 56.49; H, 2.63; Cl,9.26. Found: C, 56.35; H, 2.66; Cl, 9.34.

EXAMPLE 98

[1134]

[1135]6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1136] The 2H-1-benzopyran-3-carboxylic acid was prepared analogous tothe procedure described in Example 96: mp 234.0-239.5° C. ¹H NMR(acetone-d₆/300 MHz) 8.03 (s, 1H), 7.92 (d, 1H, J=2.0 Hz), 7.83 (dd, 1H,J=8.5 Hz 2.0 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.20 (d, 1H, J=8.5 Hz), 7.00(d, 1H, J=8.7 Hz), 5.94 (q, 1H, J=7.1 Hz). ESHRMS m/z 363.0471 (M−H,Calc'd 363.0480).

EXAMPLE 99

[1137]

[1138] 6-Phenoxy-2-(trifluoride enzopyran-3-carboxyl

[1139] 4-Phenoxyphenol was converted to 5-phenoxysalicylaldehyde by asimilar procedure to that described in Example 2, Step 1.5-Phenoxysalicylaldehyde was converted into the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp184.9-186.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.39 (m, 2H),7.20 (d, 1H, J=2.0 Hz), 7.08 (m, 3H), 7.02 (m, 2H), 5.98 (q, 1H, J=7.2Hz). FABLRMS m/z 335 (M−H). FABHRMS m/z 337.0663 (M+H, Calc'd 337.0687).Anal. Calc'd for C₁₇H₁₁F₃O₄: C, 60.72; H, 3.30. Found: C, 60.62; H,3.29.

EXAMPLE 100

[1140]

[1141]8-Chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1142] Step 1. Preparation of 5-phenoxysalicylaldehyde.

[1143] Ethyl magnesium bromide (67.5 mL of an approximately 3.0 Msolution in diethyl ether, 202.5 mmol) was added to toluene (50 mL). Asolution of 4-phenoxyphenol (25.00 g, 134.26 mmol) in diethyl ether (35mL) was added resulting in the evolution of gas. The reaction was heatedto 80° C. causing distillation of the diethyl ether. Toluene (300 mL),HMPA (23.4 mL, 24.059 g, 134.26 mmol), and paraformaldehyde (10.07 g,335.65 mmol) were added and the reaction was heated to 85° C. for 4hours. The reaction was cooled to room temperature and was acidifiedwith 2N HCl.

[1144] The resulting layers were separated and the organic phasecollected. The organic phase was washed with brine. The combined aqueousphases were extracted with methylene chloride. The organic phases werecombined, dried over MgSO₄, filtered and concentrated in vacuo yieldinga yellow oil. The oil was purified by silica flash chromatography(hexanes-ethyl acetate, 95:5). Concentration in vacuo of the desiredfractions provided the salicylaldehyde as a pale yellow powder (12.0 g,42%) of suitable purity to use in subsequent steps.

[1145] Step 2. Preparation of3-chloro-5-(4-chlorophenoxy)salicylaldehyde.

[1146] To a stirred solution of the salicylaldehyde (Step 1)(0.981 g,4.58 mmol) in acetic acid (20 mL) was added chlorine gas via a tubeuntil the yellow color of chlorine persisted. After stirring for fourhours at room temperature the reacted with nitrogen and diluted with.The resulting oily suspension was extracted with methylene chloride. Themethylene chloride phase was washed with sodium bisulfite solution,dried over MgSO₄, filtered and concentrated in vacuo providing thedichlorinated salicylaldehyde as a yellow oil (0.66 g, 51%) of suitablepurity for use in subsequent steps without further purification.

[1147] Step 3. Preparation of ethyl8-chloro-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1148] A mixture of the dichlorinated salicylaldehyde (Step 2) (0.66 g,2.3 mmol), triethylamine (0.49 g, 4.8 mmol), ethyl4,4,4-trifluorocrotonate (0.59 g, 3.5 mmol) in dimethyl sulfoxide (5 mL)was heated to 85° C. for 3.5 hours. The reaction was allowed to cool toroom temperature and was diluted with ethyl acetate (50 mL). Theresulting mixture was washed with 3 N HCl (50 mL), aqueous potassiumcarbonate solution (10 weight %, 2×30 mL), and brine. The organic phasewas dried over MgSO₄, filtered and concentrated in vacuo yielding abrown oil. This oil was purified by flash silica chromatography(hexanes-ethyl acetate, 9:1) providing the substituted 2H-1-benzopyran(0.39 g, 39%) of suitable purity to use in subsequent steps withoutfurther purification.

[1149] Step 4. Preparation of8-chloro-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1150] To a solution of the substituted 2H-1-benzopyran ethyl ester(Step 3)(0.37 g, 0.85 mmol) in ethanol-THF (4 mL, 1:1) was added sodiumhydroxide solution (2 mL of 2.5 N, 5 mmol). After stirring for six hoursthe mixture was concentrated in vacuo. Acidification of the mixture with3 N HCl yielded a solid which was collected by vacuum filtration. Thissolid was recrystallized from ethanol-water yielding the title compoundas yellow crystals(0.134 g, 38%): mp 227.8-228.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.93 (s, 1H), 7.42 (d, 2H, J=8.9 Hz), 7.24 (s, 2H),7.12 (d, 2H, J=8.9 Hz), 5.97 (q, 1H, J=7.1 Hz). FABLRMS m/z 403 (M−H).FABHRMS m/z 405.9790 (M+H, Calc'd 405.9801). Anal. Calc'd forC₁₇H₉Cl₂F₃O₄+2.33% H₂O: C, 49, 2.45. Found: C, 49.19; H, 2.27.

EXAMPLE 101

[1151]

[1152]2-(Trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H--benzopyran-3-carboxylicacid

[1153] 4-(4-Trifluoromethylphenyl)phenol was converted to5-(4-trifluoromethylphenyl)salicylaldehyde via a procedure similar tothat described in Example 2, Step 1. The5-(4-trifluoromethylphenyl)salicylaldehyde was converted to the titlecompound by a similar procedure to that described in Example 11, Steps 2& 3: mp 153.5-154.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.71(d, 2H, J=8.9 Hz), 7.33 (s, 1H, J=2.8 Hz), 7.15 (m, 4H), 5.86 (q, 1H,J=7.1 Hz). FABLRMS m/z 403 (M−H). ESHRMS m/z 403.0399 (M−H, Calc'd403.0405). Anal. Calc'd for C₁₈H₁₀F₆O₄: C, 53.48; H, 2.49. Found: C,53.52; H, 2.55.

EXAMPLE 102

[1154]

[1155] 8-(1-Methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-c acid

[1156] 4-(4-Methoxyphenyl)phenol was converted to the title compound bya procedure similar to that described in Example 2: mp 210.5-211.5° C.¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.35 (d, 1H, J=7.7 Hz), 7.28(s, 1H, J=7.5 Hz), 7.04 (t, 1H, J=7.7 Hz), 5.85 (q, 1H, J=7.2 Hz), 3.33(sept, 1H, J=7.1 Hz), 1.25 (d, 6H, J=7.1 Hz). Anal. Calc'd forC₁₄H₁₃F₃O₃: C, 58.74; H, 4.58. Found: C, 58.65; H, 4.60.

EXAMPLE 103

[1157]

[1158]6-Chloro-8-(1-methylethyl)-2-trifluoramothyl-2H-1-benzopyran-3-carboxylicacid

[1159]8-(1-Methylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acidsample 6) was converted to the title compound by a procedure similar tothat described in Example 9. mp 185.4-189.2° C. ¹H NMR (acetone-d₆/300MHz) 7.87 (s, 1H), 7.38 (d, 1H, J=2.4 Hz), 7.34 (d, 1H, J=2.4 Hz), 5.90(q, 1H, J=7.3 Hz), 3.31 (m, 1H), 1.24 (d, 6H, J=6.8 Hz). Anal. Calc'dfor C₁₅H₁₄ClF₃O₃: C, 52.43; H, 3.77; Cl, 11.05. Found: C, 52.58; H,3.79; Cl, 10.96.

EXAMPLE 104

[1160]

[1161]6-(4-Chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1162] The 2H-1-benzopyran-3-carboxylic acid was prepared from6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example99) as the starting material by a procedure similar to that described inExample 9: mp 140.5-142.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H)7.39 (d, 2H, J=9.1 Hz), 7.25 (d, 1H, J=2.6 Hz) 7.01-7.15 (m, 4H), 5.85(q, 1H, J=7.2 Hz). FABLRMS m/z 370 (M+). ESHRMS m/z 369.0130 (M−H,Calc'd 369.0141). Anal. Calc'd for C₁₇H₁₀ClF₃O₄+0.96% H₂O: C, 54.55; H,2.80. Found: C, 54.38; H, 2.90.

EXAMPLE 105

[1163]

[1164] 8-Chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxylzopyran-3-carboxylic acid

[1165] The benzopyran-3-carboxylic acid was prepared using2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid (Example 101) as the starting material by a similar procedure tothat described in Example 100: mp 223.7-226.0° C. ¹H NMR (acetone-d₆/300MHz) 7.94 (s, 1H), 7.74 (d, 2H, J=8.5 Hz), 7.35 (m, 2H) 7.25 (d, 2H,J=8.5 Hz), 6.00 (q, 1H, J=7.0 Hz). FABLRMS m/z 437 (M−H). ESHRMS m/z437.0000 (M−H, Calc'd 437.0015). Anal. Calc'd for C₁₈H₉ClF₆O₄: C, 49.28;H, 2.07; Cl, 8.08. Found: C, 49.42; H, 2.12; Cl, 8.17.

EXAMPLE 106

[1166]

[1167] 3-(Trifluoromethyl)-3H-benzofuro[3,2-f][1]benzopyran-2-carboxylicacid

[1168] 2-Hydroxydibenzofuran was converted to the title compound by a prlar to that described in Example .6° C. ¹H NMR (acetone-d₆/300 MHz) 8.54(s, 1H), 8.23 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.62 (m, 1H), 7.50 (m,1H), 7.23 (d, 1H, J=8.9 Hz), 5.95 (q, 1H, J=7.3 Hz). FABLRMS m/z 333(M−H). ESHRMS m/z 333.0401 (M−H, Calc'd 333.0375). Anal. Calc'd forC₁₇H₉F₃O₄: C, 61.09; H, 2.71. Found: C, 60.95; H, 2.80.

EXAMPLE 107

[1169]

[1170] 6-Chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1171] Step 1. Preparation of ethyl6-chloro-8-(hydroxyiminomethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1172] Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate(1.50 g, 19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) werestirred at room temperature for 0.4 hours. The aldehyde (Example 76,Step 3)(3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water(4:1, 25 mL) and added to this mixture and stirred at 100° C. for 1hour. The reaction was filtered hot and the filtrate allowed to cool toroom temperature. An orange solid crystallized in the filtrate which wascollected by vacuum filtration. The solid was dissolved in ethyl acetateand the solution washed with water, brine, dried over MgSO₄,concentrated in vacuo. The resulting solid was recrystallized from ethylacetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp186.6-187.6° C. ¹H NMR (acetone-d₆/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H),7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q,1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).

[1173] Step 2. Preparation of ethyl6-chloro-8-cyano-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

[1174] The oxime from Step 1 (0.61 g, 1.7 mmol) and acetic anhydride (6mL) were stirred at 140 ° C. for 6.3 hours. The reaction was poured intowater, extracted with ethyl acetate, washed with saturated NaHCO₃,brine, dried over MgSO₄, and concentrated in vacuo to give a brown oil(1.09 g). The oil was purified by flash chromatography (10:1; hexanes:ethyl acetate) yielding upon concentration the title compound as a whitesolid (0.51 g, 88%): mp 114.6-115.6° C. ¹H NMR (CDCl₃/300 MHz) 7.65 (s,1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.87 (q, 1H, J=6.4Hz), 4.36 (m, 2H), 1.37 (t, 3H, J=6.5 Hz).

[1175] Step 3. Preparation of6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

[1176] The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5mL) and ethanol (5 mL), treated with 2.5N sodium hydroxide (1.2 mL, 3.0mmol), and stirred at room temperature for 1.5 hours. The reactionmixture was concentrated in vacuo, acidified with 3N HCl, extracted withethyl acetate, washed with water, brine, dried over MgSO₄, concentratedin vacuo, and recrystallized from diethyl ether/hexane to give a whitepowder (0.10 g, 21%): mp 238.1-239.7° C. ¹H NMR (acetone-d₆/300 MHz)7.97 (s, 1H), 7.92 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz), 6.14 (q,1H, J=6.6 Hz). FABLRMS m/z 302 (M−H). ESHRMS m/z 301.9819 (M−H, Calc'd301.9832). Anal. Calc'd for C₁₂H₅ClF₃NO₃: C, 47.47; H, 1.66; N, 4.61.Found: C, 47.41; H, 1.70; N, 4.55.

EXAMPLE 108

[1177]

[1178]6-Chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1179] The 2H-1-benzopyran-3-carboxylic acid was prepared from the ethylester (Example 107, Step 2) by a method similar to the proceduredescribed in Example 1, Step 2: mp 246.9-247.9° C. ¹H NMR(acetone-d₆/300 MHz) 10.90 (brs, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 7.78(d, 1H, J=2.6 Hz), 7.61 (d, 1H, J=2.6 Hz). 5.98 (q, 1H, J=7.0 Hz).FABLRMS m/z ). ESHRMS m/z 319.9959 (M−H, 9.9937). Anal. Calc'd forC₁₂H₇Cl , 44.81; H, 2.19; N, 4.35. Found: C, 44.92; H, 2.25; N, 4.26.

EXAMPLE 109

[1180]

[1181]6-Chloro-8-(hydroxymethyl)-2-(trifluoramethyl)-2H-1-benzopyran-3-carboxylicacid

[1182] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 80 using the carboxylic acid(Example 76, step 4) as the starting material: mp 174.6-178.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.57 (d, 1H, J=2.6 Hz), 7.47 (d, 1H,J=2.6 Hz), 5.87 (q, 1H, J=7.0 Hz), 4.70 (s, 2H). FABLRMS m/z 309 (M+H).ESHRMS m/z 306.9981 (M−H, Calc'd 306.9985). Anal. Calc'd for C₁₂H₈ClF₃O₃(3.81 wt. % H₂O): C, 47.37; H, 3.08. Found: C, 47.33; H, 2.82.

EXAMPLE 110

[1183]

[1184]8-(1H-Benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1185] Step 1. Preparation of ethyl8-(1H-Benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1186] A solution of the aldehyde (Example 76, Step 3)(0.33 g, 0.99mmol) and 1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20mL) was heated to 150° C. for 1.8 hours. The reaction mixture wasextracted with ethyl acetate, washed with brine, dried over MgSO₄, andconcentrated in vacuo and purified by flash chromatography over silicagel (with 1:9 ethyl acetate/hexane as eluant) to give the ester as abrown solid (0.18 g, 43%) which was used in the next step withoutfurther purification.

[1187] Step 2. Preparation of8-(1H-enzimidazol-2-yl)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

[1188] The ester from Step 1 (0.18 g 1.5 mmol) was dissolved in THF (5mL) and ethanol (5 mL), treated with 2.5 N sodium hydroxide (2.6 mL, 6.5mmol), and stirred at room temperature for 1.7 hours. The reactionmixture was concentrated in vacua, acidified with 3 N HCl, filtered andrecrystallized from ethanol-water to give a tan solid (0.09 g, 52%):mp >300° C. ¹H NMR (acetone-d₆/300 MHz) 8.59 (d, 1H, J=2.6 Hz), 8.03 (s,1H), 7.73 (d, 1H, J=2.6 Hz), 7.67 (brs, 2H), 7.28 (m, 2H), 6.13 (q, 1H,J=6.8 Hz). FABLRMS m/z 395 (M−H{³⁷Cl}). ESHRMS m/z 393.0262 (M−H, Calc'd393.0254). Anal. Calc'd for C₁₈H₁₀ClF₃N₂O₃ (2.88 wt % H₂O) : C, 53.19;H, 2.80; N, 6.89. Found: C, 53.22; H, 2.90; N, 6.80.

EXAMPLE 111

[1189]

[1190]7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid

[1191] Step 1. Preparation of ethyl3-hydroxy-4,4,5,5,5-pentafluoropentanoate.

[1192] A solution of ethyl 4,4,5,5,5-pentafluoro-3-oxo-pentanoate (41.32g, 0.18 mole) in diethyl ether (70 mL) was cooled to 0° C. and treatedwith NaBH₄ (7.09 g, 0.19 mole). The reaction was allowed to warm to roomtemperature and stirred for 2 hours before quenching with 1 N HCl (200mL). The layers were separated and the aqueous layer was extracted withdiethyl ether. The combined organic layers were washed with 1 N HCl,brine, dried over MgSO₄, and concentrated in vacuo to give the hydroxyester as a clear oil (46.40 g) which was used in the next step withoutfurther purification.

[1193] Step 2. Preparation of ethyl 4,4,5,5,5-pentafluoro-2-pentenoate.

[1194] The hydroxy ester from Step 1 (46.40 g, 0.18 mole) was stirred at120° C. with P₂O₅ (25.59 g, 0.09 mole) for 2.6 hours then vacuumdistilled (95 torr, 45-64° C.) to give the ester as a clear oil (13.70g, 35%): ¹H NMR (CDCl₃/300 MHz) 6.78 (m, 1H), 6.57 (dt, 1H, J=15.9 Hz2.0 Hz), 4.30 (q, 2H, J=7.3 Hz), 1.34 (t, 3H, J=7.1 Hz).

[1195] Step 3. Preparation of ethyl7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylate.

[1196] A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15g, 6.4 mm nd the ethyl ester from Step 2 (1.59 g, 7.3 mmol) wasdissolved in anhydrous DMF (4 mL). With stirring, K₂CO₃ (1.10 g, 9.0mmol) was added causing the reaction to become deep red. The reactionwas stirred at room temperature for 100 hours, acidified with 3 N HCl,diluted with ethyl acetate and washed with saturated NaHCO₃ solution,brine, dried over MgSO₄, filtered and concentrated in vacuo yielding abrown oil. This oil was purified by flash chromatography over silicagel, eluting with 10% ethyl acetate/hexanes to afford a yellow oil (1.72g, 70%): ¹H NMR (CDCl₃/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz),7.04 (dd, 1H, J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H).

[1197] Step 4. Preparation of7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid.

[1198] The ester from Step 3 (1.58 g 4.20 mmol) was dissolved in THF (3mL) and ethanol (3 mL), treated with 2.5 N sodium hydroxide (2 mL, 5mmol), and stirred at room temperature for 23.3 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl yielding asuspension. The solid was collected by filtration and was recrystallizedfrom ethanol-water to yield a yellow solid (0.76 g, 52%): mp171.0-173.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.93 (s, 1H), 7.39 (d, 1H,J=8.1 Hz), 7.18 (dd, 1H, J=8.1 Hz 1.8 Hz), 7.02 (s, 1H), 6.01 (dd, 1H,J=23.1 Hz 3.2 Hz), 1.32 (s, 9 H). FABLRMS m/z 351 (M+H). E1HRMS m/z350.0945 (M+, Calc'd 350.0941). Anal. Calc'd for C₁₆H₁₅F₅O₃: C, 54.86;H, 4.32. Found: C, 54.88; H, 4.32.

EXAMPLE 112

[1199]

[1200]6-Chloro-8-(methoxymethyl)-2-(trifluoremethyl)-2H-1-benzopyran-3-carboxylicacid

[1201] Step 1. Preparation of ethyl6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1202] A suspension of the aldehyde (Example 75, Step 1) (4.78 g, 14.3mmol) was cooled to 0° C. and treated with NaBH, (0.33 g, 4.8 mmol). Thesolution was stirred for 10 minutes then quenched with 3N HCl, extractedwith ethyl acetate, washed with saturated NaHCO₃, brine, dried overMgSO₄, and concentrated in vacuo to give a brown solid which wasfiltered through a plug of silica gel to give the alcohol as a brownsolid (3.60 g, 75%). ¹H NMR (CDCl₃/300 MHz) 7.66 (s, 1H), 7.41 (d, 1H,J=2.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 5.75 (q, 1H, J=6.8 Hz), 4.71 (s, 2H),4.33 (m, 2H), 1.85 (brs, 1H), 1.36 (t, 3H, J=7.1). This solid was usedin the next step without further purification.

[1203] Step 2. Preparation of ethyl6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1204] The alcohol from Step 1 (0.44 g, 1.3 mmol), silver triflate (0.36g, 1.4 mmol) and 2,6-di-tert-butylpyridine (0.37 g, 1.9 mmol) weredissolved in methylene chloride (3 mL) cooled to 0° C. and treated withmethyl iodide (0.40 g, 2.8 mmol). The reaction was allowed to warm andstirred at room temperature for 4.6 hours. The reaction was filteredthrough diatomaceous earth and the filtrate was washed with 3N HCl,saturated NaHCO₃, brine, dried over MgSO₄, and concentrated in vacuoyielding a brown oil. This oil was purified by flash chromatography oversilica gel, eluting with 10% ethyl acetate-hexanes to afford thesubstituted 2H-1-benzopyran (0.19 g, 41%) as a white oily solid suitable

[1205] ESHRMS m/z 321.0141 (M−H, Calc'd 321.0141). Anal. Calc'd forC₁₃H₁₀ClF₃O₄: C, 48.39; H, 3.12. Found: C, 48.45; H. 3.11.

EXAMPLE 113

[1206]

[1207]6-Chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1208] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 112: mp 133.8-135.4° C. ¹HNMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.54 (d, 1H, J=2.6), 7.51 (d, 1H,J=2.4 Hz), 7.4 , 5H), 5.91 (q, 1H, J=7.1 Hz), 4.68 (s, 2H), 4.63 (s,2H). FABLRMS m/z 399 (M+H). ESHRMS m/z 397.0454 (M−H, Calc'd 397.0461).Anal. Calc'd for C₁₉H₁₃ClF₃O₄: C, 57.23; H, 3.54; Cl, 8.89. Found: C,57.34; H, 3.63; Cl, 8.77.

EXAMPLE 114

[1209]

[1210]6-Chloro-8-ethenyl-2-(trifluoramethyl)-2H-1-benzopyran-3-carboxylic acid

[1211] Step 1. Preparation ofethenyl-6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1212] In a 100 mL round bottomed flask under N₂, ethyl8-bromo-6-chloro-2-trifluoromethyl-2H-benzopyran-3-carboxylate (Example74, Step 1)(2.21 g, 5.73 mmol) was dissolved in toluene (30 mL ofanhydrous reagent). Tetrakis(triphenylphosphine)palladium(0) (0.132 g,0.115 mmol) was added, followed by tributylethyenylstannane (2.0 g, 6.31mmol). The resulting solution was heated to reflux for 5 hours. Thereaction mixture was allowed to cool to room temperature, was pouredinto 50 mL of 20% ammonium fluoride solution and for one hour. Diethylether (100 and the mixture was washed with water (2×50 mL). The organicphase was dried over MgSO₄, filtered, and evaporated to yield a yellowoil. The crude material was purified by flash chromatography(0.5% ethylacetate in hexanes) to afford the ester as a yellow solid (0.86 g, 45%):mp 75.9-77.2° C. ¹H NMR (CDCl₃/300 MHz) 7.64 (s, 1H), 7.45 (d, 1H, J=2.5Hz), 7.12 (d, 1H, J=2.6 Hz), 6.92 (dd, 1H, J=17.7 Hz, 11.3 Hz), 5.81 (d,1H, J=17.7 Hz), 5.76 (q, 1H, J=6.8 Hz), 5.41 (d, 2H, J=11.1 Hz),4.36−4.29 (m, 2H), 1.36 (t, 3H, J=7.3 Hz). FABLRMS m/z 350.1 (M+NH₄ ⁺).ESHRMS m/z 350.0796 (M+NH₄ ⁺, Calc'd. 350.0771). Anal. Calc'd. forC₁₅H₁₂ClF₃O₃+4.07% H₂O: C, 51.95; H, 3.94. Found: C, 51.67; H, 3.69.

[1213] Step 2. Preparation of6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1214] The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in asolution of THF:ethanol:water(7:2:1; 10 mL), was treated with sodiumhydroxide (0.46 mL, 1.05 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was removed in vacuo and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL) was addedand the mixture acidified with concentrated HCl. The layers wereseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The organic phases were combined, dried over MgSO₄, filtered, andevaporated to yield a yellow solid, which was recrystallized in diethylether-hexane to afford the title compound as a yellow solid (0.288 g,90%): mp 183.2-185.8° C. ¹H NMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.49 (d,1H, J 7.16 (d, 1H, J=2.4 Hz), 6.93 (dd, =11.3, 17.7 Hz), 5.82 (d, 1H,J=17.7 Hz), 5.74 (q, 1H, J=6.9 Hz), 5.43 (d, 1H, J=11.1 Hz). FABLRMS m/z303 (M−H). ESHRMS m/z 303.0014 (M−H, Calc'd. 303.003582). Anal. Calc'd.for C₁₃H₈ClF₃O₃+1.58% H₂O: C, 50.44; H, 2.78. Found: C, 50.42; H, 2.65.

EXAMPLE 115

[1215]

[1216]6-Chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1217] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 186.2-189.0° C. ¹HNMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.60 (d, 1H, J=2.4 Hz), 7.51 (d,1H, J=2.4 Hz), 5.95 (q, 1H, J=7.0 Hz), 4.02 (s, 1H). FABLRMS m/z 301(M−H). ESHRMS m/z 300.9875 (M−H, Calc'd 300.9879). Anal. Calc'd. forC₁₃H₆ClF₃O₃: C, 51.59; H, 2.00; Cl, 11.71. Found: C, 51.26; H, 2.06; Cl,11.40.

EXAMPLE 116

[1218]

[1219]6-Chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1220] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 257.5-258.8° C. ¹HNMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.74−7.72(m, 1H), 7.62−7.61 (m, 1H), 7.51 (d, 1H, J=2.4 Hz), 7.19−7.16 (m, 1H),6.04 (q, 1H, J=7.1 Hz). FABLRMS m/z 359 (M−H). ESHRMS m/z 358.9747 (M−H,Calc'd. 358.9756). Anal. Calc'd. for C₁₅H₈ClF₃O₃S: C, 49.94; H, 2.24;Cl, 9.83; S, 8.89. Found: C, 50.26; H, 2.45; Cl, 9.72; S, 9.00.

EXAMPLE 117

[1221]

[1222] 6-Chloro-8-(2-furanyl)-fluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1223] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 171.5-173.3° C. ¹HNMR (acetone-d₆/300 MHz) 7.93 (s, 1H), 7.82 (d, 1H, J=2.6 Hz), 7.72−7.71(m, 1H), 7.50 (d, 1H, J=2.6 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.65−6.63 (m,1H), 6.11 (q, 1H, J=7.1 Hz). FABLRMS m/z 343 (M−H). ESHRMS m/z 342.9995(M−H, Calc'd. 342.9985). Anal. Calc'd. for C₁₅H₈ClF₃O₄+1.31% H₂O: C,51.59; H, 2.46; Cl, 10.15. Found: C, 51.57; H, 2.33; Cl, 10.14.

EXAMPLE 118

[1224]

[1225]6-Chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1226] Step 1. Preparation of ethyl6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1227] Ethyl6-chloro-8-iodo-2-trifluromethyl-2H-1-benzopyran-3-carboxylate (Example73, Step 2) (1.50 g, 3.47 mmol),tetrakis-(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol),copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g,5.20 mmol) was added via syringe and the mixture stirred for 18 hours atroom temperature. The reaction was diluted with diethyl ether (50 mL),extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organicphase was dried over MgSO₄, filtered, and evaporated to yield an orangeoil. The crude material was purified by flash chromatography in 2% ethylacetate in hexane. Recrystallization from hexane afforded the ester as awhite solid (0.96 g, 68%): mp 84.8-85.9° C. ¹H NMR (CDCl₃/300 MHz) 7.61(s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H,J=6.7 Hz), 4.37−4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7Hz), 2.11−2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1(M+NH₄ ⁺). ESHRMS m/z 424.0694 (M+NH₄ ⁺, Calc'd. 424.0694). Anal.Calc'd. for C₁₈H₁₅Cl₂F₃O₃: C, 53.09; H,3.71;, Cl,17.41. Found: C, 53.02;H, 3.90; Cl, 17.63.

[1228] Step 2. Preparation of6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1229] The ester (Step 1) (0.500 g, 1.23 mmol) was dissolved inTHF-ethanol-water(7:2:1; 10 mL). It was treated with sodium hydroxide(0.49 mL, 1.23 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was evaporated and the residue wasdissolved in water (10 mL). Diethyl ether (10 mL) was added and themixture acidified with concentrated HCl. The organic layer wasseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The combined extracts were dried over MgSO₄, filtered, andevaporated to yield a yellow solid, which was recrystallized in diethylether-hexane to afford the title compound as a yellow solid (0.371 g,80%): mp 154.4-156.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.88 (s, 1H), 7.53(d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.94 (q, 1H, J 7.1 Hz), 3.83(t, 2H, J=6.5 Hz), 2.68 (t, 2H, J=6.8 Hz), 2.12−2.04 (m, 2H). ESLRMS m/z377 (M−H). ESHRMS m/z 376.9930 (M−H, Calc'd. 376.9959). Anal. Calc'd.for C₁₆H₁₁Cl₂F₃O₃+1.18% H₂O: C, 50.08; H, 3.02; Cl, 18.48. Found: C,50.11; H, 2.73; Cl, 18.28.

EXAMPLE 119

[1230]

[1231]6-Chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1232] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 168.1-171.2° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.37 (d, 1H, J=2.6 Hz), 7.15 (d, 1H,J=2.4 Hz), 5.77 (1, 1H, J=6.7 Hz), 2.44 (t, 2H, J=6.9 Hz), 1.68−1.61 (m,2H), 1.07 (t, 3H, J=7.25 Hz. FABLRMS m/z 345 (M+H). ESHRMS m/z 343.0373(M−H, Calc'd. 343.0349). Anal. Calc'd. for C₁₆H₁₂ClF₃O₃+0.69% H₂O: C,55.36; H, 3.56. Found: C, 55.21; H, 3.62.

EXAMPLE 120

[1233]

[1234]6-Chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1235] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 190.1-192.1° C. ¹HNMR (CDCl₃/300 MHz) 7.92 (s, 1H), 7.61−7.57 (m, 4H), 7.47−7.44 (m, 3H),6.01 (q, 1H, J=7.0 Hz). ESLRMS m/z 377 (M−H). ESHRMS m/z 377.0167 (M−H,Calc'd. 377.0192). Anal. Calc'd. for C₁₉H₁₀ClF₃O₃: C, 60.26; H, 2.66;Cl, 9.36. Found: 60.09; H, 2.73; Cl, 9.09.

EXAMPLE 121

[1236]

[1237]6-Chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1238] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 218.3-222.4° C. ¹HNMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.51 (d, 1H, J=2.4 Hz), 7.38 (d,1H, J=2.6 Hz), 5.92 (q, 1H, J=6.9 Hz), 1.32 (s, 9H). FABLRMS m/z 359(M+H). ESHRMS m/z 357.0490 (M−H, Calc'd. 357.0505). Anal. Calc'd. forC₁₇H₁₄ClF₃O₃: C, 56.92; H, 3.93; Cl, 9.88. Found: C, 56.63; H, 3.94; Cl,10.03.

EXAMPLE 122

[1239]

[1240]6-Chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1241] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 210.4-211.4° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.48−7.43 (m, 3H), 7.36 (s, 1H), 7.33(s, 1H), 7.22 (d, 1H, J=2.6 Hz), 5.82 (q, 1H, J=6.6 Hz). FABLRMS m/z 411(M−H). ESHRMS m/z 410.9802 (M−H, Calc'd. 410.980259). Anal. Calc'd. forC₂₀H₁₂C₁₂F₃O₃: C, 55.23; H, 2.20; Cl, 17.16. Found: C, 55.22; H, 2.07;Cl, 17.39.

EXAMPLE 123

[1242]

[1243]6-Chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1244] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 217.7-218.7° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.51−7.47 (m, 3H), 7.18 (d, 1H, J=2.4Hz), 6.91−6.88 (m, 2H), 5.82 (1, 1H, J=6.7 Hz). ESLRMS m/z 407 (M−H).ESHRMS m/z 407.0293 (M−H, Calc'd 407.0298). Anal. Calc'd forC₂₀H₁₂ClF₃O₄: C, 58.77; H, 2.96; Cl, 8.67. Found: C, 58.68; H, 2.85; Cl,9.15.

EXAMPLE 124

[1245]

[1246]6-(Phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1247] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 240.1-241.3° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.70−7.69 (m, 1H), 7.61−7.53 (m, 3H),7.44−7.41 (m, 3H), 7.10 (d, 1H, J=7.1 Hz). ESHRMS m/z 343.0550 (M−H,Calc'd. 343.0582). Anal. Calc'd. for C₁₉H₁₁F₃O₃: C, 66.29; H, 3.22.Found: C, 66.26; H, 3.29.

EXAMPLE 125

[1248]

[1249]6-Chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1250] Step 1. Preparation of ethyl6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1251] Ethyl6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g,9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.174 g, 0.151 mmol) wereadded to toluene (30 mL) and the resulting solution was heated to refluxfor 18 hours. After cooling to room temperature the reaction mixture waspoured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL),saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuoto yield a brown oil. The crude material was purified by flashchromatography using 1% ethyl acetate in hexane yielding a white solid.Recrystallization from hexane afforded the ester as a white solid (0.79g, 64%): mp 114.2-115.9° C. ¹H NMR (CDCl₃/300 MHz) 7.69 (s, 1H), 7.41(s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H,J=6.9 Hz), 4.37−4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434(M+NH₄ ⁺). FABHRMS m/z 434.0574 (M+NH₄ ⁺, Calc'd. 434.0538). Ana c'd.for C₁₉H₁₃Cl₂F₃O₃: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H,3.18; Cl, 16.65.

[1252] Step 2. Preparation of6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1253] The ester from Step 1 (0.500 g, 1.20 mmol) was dissolved in asolution of THF:ethanol:water (7:2:1; 10 mL), treated with sodiumhydroxide (0.48 mL, 1.20 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was removed in vacuo and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL) was addedand the mixture acidified with concentrated HCl. The organic layer wasseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The combined extracts were dried over MgSO₄, filtered, andevaporated to yield a white solid, which was recrystallized in diethylether-hexane to afford the title compound as a white solid (0.40 g,86%): mp 205.5-207.3° C. ¹H NMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.42(s,4H), 7.34 (d, 1H, J=2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J=6.8 Hz).FABLRMS m/z 387 (M−H). ESHRMS m/z 386.9788 (M−H, Calc'd. 386.980259).Anal. Calc'd. for C₁₇H₉Cl₂F₃O₃: C, 52.47; H, 2.33; Cl, 18.22. Found: C,52.38; H, 2.47; Cl, 18.20.

EXAMPLE 126

[1254]

[1255]6-Chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1256] Step 1. Preparation of ethyl6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1257] In a 100 mL round bottomed flask under nitrogen, ethyl6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 73, Step 2)(1.00 g, 2.31 mmol) and 3-methoxyphenylboronic acid(0.369 g, 2.43 mmol) were dissolved in 1-propanol (50 mL). The mixturewas stirred at room temperature for 0.5 hours, allowing for the solidsto dissolve. The resulting solution was treated with palladium (II)acetate (0.016 g, 0.0693 mmol), triphenylphosphine (0.055 g, 0.208mmol), sodium carbonate (0.294 g, 2.77 mmol), and deionized water (10mL). The reaction mixture was heated to reflux for 3 hours. Aftercooling to room temperature the mixture was extracted with ethyl acetate(1×150 mL, 2×25 mL). The combined organic phases were washed withsaturated aqueous NaHCO₃ (50 mL) and brine (2×50 mL), dried over MgSO₄,filtered, and concentrated in vacuo to yield a yellow oil. The crudematerial was purified by flash chromatography in 0.5% ethyl acetate inhexane yielding a white solid. The solid was recrystallized from hexaneyielding the desired ester as a white solid (0.60 g, 63%): mp 93.7-95.1°C. ¹H NMR (CDCl₃/300 MHz) 7.69 (s, 1H), 7.35−7.32 (m, 2H), 7.22 (d, 1H,J=2.6 Hz), 7.05−7.03 (m, 2H), 6.96−6.93 (m, 1H), 5.72 (q, 1H, J=6.7 Hz),4.34−4.31 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). FABLRMS m/z 413 (M+H). ESHRMSm/z 413.0765 (M+H, Calc'd. 413.076747). Anal. Calc'd. for C₂₀H₁₆ClF₃O₄:C, 58.19; H, 3.91; Cl, 8.59. Found: C, 58.33; H, 4.10; Cl, 8.61.

[1258] Step 2. Preparation of6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1259] The ester from Step 1 (0.300 g, 0.727 mmol) was dissolved inTHF-ethanol-water (7:2:1, 10 mL). It was treated with sodium hydroxide(0.29 mL of a 2.5 N solution, 0.727 mmol), and stirred at roomtemperature for 18 hours. The solvent was evaporated and the residue wasdissolved in water (10 mL). Ether (10 mL) was added, followed by a fewdrops of concentrated HCl. The ether layer was separated, and theaqueous phase was extracted with ether (2×10 mL). The ether extractswere combined, dried over MgSO₄, filtered, and concentrated in vacuo toyield a white solid, which was recrystallized in diethyl ether-hexane toafford the title compound as a white solid (0.23 g, 81%): mp173.1-177.4° C. ¹H NMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.39−7.37 (m, 2H(m, 2H), 6.97−6.94 (m, 1H), 5.71 (q Hz), 3.85 (s, 3H). ESHRMS m/z383.0278 (M−H, Calc'd. 383.029796). Anal. Calc'd. for C₁₈H₁₂ClF₃O₄: C,56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl, 9.48.

EXAMPLE 127

[1260]

[1261]6-Chloro-8-[(4-methylthio)phenyl]-2-(trifluoramethyl)-2H-1-benzopyran-3-carboxylicacid

[1262] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: mp 211.4-212.5° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.57 (d, 1H, J=2.6 Hz), 7.53−7.50(m, 2H), 7.45 (d, 1H, J=2.6 Hz), 7.39−7.36 (m, 2H), 5.87 (q, 1H, J=7.1Hz), 2.55 (s, 3H). ESHRMS m/z 399.0051 (M−H, Calc'd. 399.0069). Anal.Calc'd. for C₁₈H₁₂ClF₃O₃S: C, 53.94; H, 3.02; Cl, 8.84; S, 8.00. Found:C, 53.86; H, 2.82; Cl, 8.91; S, 8.21.

EXAMPLE 128

[1263]

[1264]6-Chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1265] Step 1. Preparation ofethyl-6-chloro-8-[(4-methyl-sulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1266] Oxonel (1.44 g, 2.34 mmol) was dissolved in H₂O (10 mL) and thenchilled to 5° C. A solution of ethyl6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 127, ethyl ester) (0.5 g, 1.17 mmol)in methanol (20 mL) wasslowly added to the reaction mixture and the solution was stirred atroom temperature for 5 hours. The methanol was then removed in vacuo.The remaining solution was extracted with methylene chloride (2×50 mL).The combined organic layers were dried over MGSO₄, filtered, andevaporated to yield a yellow solid. This solid was recrystallized inether-hexane to afford the sulfone as a white solid (0.46 g, 84%): mp139.2-146.2° C. ¹H NMR (CDCl₃/300 MHz) 8.03(s, 1H), 8.00 (s, 1H), 7.70(d, 2H, J=2.4 Hz), 7.28 (d, 1H, J=2.6 Hz), 5.71 (q, 1H, J=6.9 Hz),4.35−4.32 (m, 2H), 3.11(s, 3H), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 467(M+Li). ESHRMS m/z 478.0707 (M+NH₄+, Calc'd. 478.070281). Anal. Calc'd.for C₂₀H₁₆ClF3O₅S: C, 52.12; H, 3.50; Cl, 7.69. Found: C, 52.17; H,3.36; Cl, 7.77.

[1267] Step 2. Preparation of6-chloro-8-[(4-methylsulfonyl)phenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1268] The sulfone from Step 1 (0.300 g, 0.651 mmol) was dissolved in asolution of THF:ethanol:water (7:2:1; 10 mL). It was treated with sodiumhydroxide (0.26 mL, 0.651 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was removed in vacuo and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL) was andthe mixture acidified with concentrated HCl. The organic layer wasseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The combined organic extracts were dried over MgSO₄, filtered, andevaporated to yield a white solid. Recrystallization of this solid inether-hexane afforded the title compound as a white solid (0.20 g, 73%):mp 286.5-287.8° C. ¹H NMR (acetone-d₆/300 MHz) 8.07 (d, 2H, J=6.7 Hz),7.97 (s, 1H), 7.84 (d, 2H, J=6.7 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.55 (d,1H, J=2.6 Hz), 5.92 (q, 1H, J=7.1 Hz), 3.20 (s, 1H). ESHRMS m/z 430.9947(M−H, Calc'd. 430.996782). Anal. Calc'd. for C₁₈H₁₂ClF₃O₅S: C, 49.95; H,2.80; Cl, 8.19. Found: C, 50.04; H, 2.80; Cl, 8.25.

EXAMPLE 129

[1269]

[1270]6-Chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1271] Step 1. Preparation of ethyl6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1272] A mixture of ethyl6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 74, Step 1)(2.0 g, 5.2 mmol), tetrakis(triphenylphosphine)palladium(0) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) washeated to 110° C. for 3 days. The reaction mixture was allowed to coolto room temperature and filtered through a plug of silica gel elutingwith 25% ethyl acetate in hexanes. The filtrate was concentrated invacua and then purified by flash chromatography (silica gel, ethylacetate-hexanes, 1:9). The fractions containing desired product werecombined and concentrated in vacua. To remove the remaining tinimpurities the mixture was taken up in THF (10 mL) and aqueous ammoniumfluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2hours. The solution was extracted with ethyl acetate. The extracts werecombined, dried over MgSO₄, filtered, and concentrated in vacua toafford the ester as an oil (1.30 g, 65%). ¹H NMR(CDCl₃/300 MHz) 7.67 (s,1H),7.47−7.36 (m, 5H), 7.31 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=2.4 Hz),5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J=7.1 Hz). ¹⁹FNMR(CDCl₃/282 MHz) d −78.27 (d, J=7.2 Hz). FABLRMS m/z 383 (M+H). ESHRMSm/z 400.0937 (M+NH₄, Calc'd 400.0927)

[1273] Step 2. Preparation of6-chloro-8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[1274] A solution of the ester from step 1 (1.0 g, 2.6 mmol) wasdissolved in THF (5 mL) and methanol (5 mL) was treated with a 2.5 NNaOH solution (4.0 mL, 10.4 mmol). The resulting mixture was stirred atroom temperature for 18 hours. The solvent was removed in vacuo, and theresidue taken up in ethyl acetate and acidified with 3 N HCl. Thesolution was extracted with ethyl acetate. The extracts were combined,dried over MgSO₄, filtered, and concentrated in vacuo yielding a yellowsolid. Recrystallization from ethyl acetate-hexanes afforded the titlecompound as a pale yellow solid (0.42 g, 46%): mp 196.3-197.7° C. ¹H NMR(CDCl₃/300 MHz) d 7.65 (s, 1H), 7.40−7.23 (m, 6H), 7.15 (s, 1H), 5.63(q, 1H, J=6.5 Hz), 3.35 (broad s, 1H). ¹⁹F NMR (CDCl₃/282 MHz)d −78.71(d, J=5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M−H, Calc'd353.0192).

EXAMPLE 130

[1275]

[1276] 6-Bromo-9-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1277] 4-Bromo-2-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 206-208° C. ¹H NMR(CD₃OD/300 MHz) 7.78 (s, 1H), 7.36-7.48 (m, 2H), 5.87 (q, 1H, J=6.8 Hz).EIHRMS m/z 339.9349 (Calc'd 339.9358). Anal. Calc'd for C₁₁H₅BrF₄O₃: C38.74, H 1.48; Found C 38.97, H, 1.60.

EXAMPLE 131

[1278]

[1279]6-(4-Fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1280] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material:_mp 207-210° C. ¹H NMR (CD₃OD/300 MHz)7.87 (s, 1H), 7.54-7.64 (m, 4H), 7.10-7.20 (m, 2H), 7.03 (d, 1H, J=9.4Hz), 5.77 (q, 1H, J=7.0 Hz). EIHRMS m/z 338.0573 (Calc'd 338.0566) Anal.Calc'd for C-₁₁H₆F₃IO₃+1.25% H₂O: C, 59.62; H, 3.08. Found C, 59.61; H,3.09.

EXAMPLE 132

[1281]

[1282] 6-Phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1283] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125_using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 197-198° C. ¹H NMR (CD₃OD/300 MHz)7.87 (s, 1H), 7.28-7.64 (m, 7H), 7.03 (d, 1H, J=6.8 Hz), 5.76 (q, 1H,J=7.0 Hz). EIHRMS m/z 320.0604 (M+, Calc'd 320.0660). Anal. Calc'd forC₁₇H₁₁F₃O₃: C, 63.75; H 3.46. Found C, 63.56; H, 3.46.

EXAMPLE 133

[1284]

[1285]8-Chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1286]

[1287]2-Chloro-4-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 240-241° C. ¹H NMR(CD₃OD/300 MHz) 7.77 (s, 1H), 7.26 (dd, 1H, J=8.3, 2.9), 7.14 (dd, 1H,J=8.1, 2.9), 5.87 (q, 1H, J=6.8 Hz). EIHRMS m/z 295.9836 (Calc'd295.9863). Anal. Calc'd for C₁₁H₅ClF₄O₃: C, 44.54; H, 1.70. Found C,44.70; H, 1.73.

EXAMPLE 134

[1288]

[1289] 6,8-Diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1290] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 1: mp 243-244° C. ¹H NMR(CD₃OD/300 MHz) 8.07 (d, 1H, J=2.0 Hz), 7.71 (s, 1H), 7.70 (d, 1H, J=2.0Hz), 5.89 (q, 1H, J=6.8 Hz). ESHRMS m/z 494.8174 (Calc'd for M−H494.8202) Anal. Calc'd for C₁₁H₅F₃I₂O₃: C, 26.64; H, 1.02. Found C,26.75; H, 1.06.

EXAMPLE 135

[1291]

[1292]6-(5-Chloro-2-thienyl)-2-(trifluoramethyl)-2H-1-benzopyran-3-carboxylicacid

[1293] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72,Step 3) as the starting material: mp 205-206° C. ¹H NMR (CD₃OD/300 MHz)7.83 (s, 1H), 7.50-7.58 (m, 2H), 7.14 (d, 1H, J=4.0 Hz), 7.00 (d, 1H,J=8.86 Hz), 6.93 (d, 1H, J=4.0 Hz), 5.77 (q, 1H, J=7.0 Hz). EIHRMS m/z359.9810 (M+, Calc'd 359.9835). Anal. Calc'd for C₁₅H₈ClF₃O₃S: C, 49.94;H 2.24. Found C, 50.14; H, 2.29.

EXAMPLE 136

[1294]

[1295] 6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1296] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 209-212° C. ¹H NMR (CD₃OD/300 MHz)7.83 (s, 1H), 7.58-7.62 (m, 2H), 7.30-7.38 (m, 2H), 6.80-7.09 (m, 2H),5,76 (q, 1H, J=7.0 Hz) FABHRMS m/z 325.0153 (Calc'd for M−H 325.0146)

EXAMPLE 137

[1297]

[1298]6-(4-Chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1299] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 212-213° C. 1H NMR (CD₃OD/300 MHz)7.89 (s, 1H), 7.56-7.66 (m, 4H), 7.40-7.48 (m, 2H), 7.04-7.10 (m, 1H),5.77 (q, 1H, J=7.0 Hz). ESHRMS m/z 353.0190 (Calc'd for M−H 353.0192).Anal. Calc'd for C₁₇H₁₀ClF₃O₃: C, 57.56; H, 2.84. Found C, 57.41; H,2.82.

EXAMPLE 138

[1300]

[1301]6-(4-Bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1302] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 215-216° C. ¹H NMR (CD₃OD/300MHz)7.89 (s, 1H), 7.06-7.71 (m, 6H), 7.04-7.06 (m, 1H), 5.78 (q, 1H,J=6.8 Hz). ESHRMS m/z 396.9681 (Calc'd for M−H 396.9687).

EXAMPLE 139

[1303]

[1304] 6-(Ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1305] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 198-200° C. ¹H NMR (CD₃OD/300 MHz)7.80 (s, 1H), 7.47 (dd, 1H, J=8.5, 2.0 Hz), 7.41 (d, 1H, J=2.0 Hz), 6.97(d, 1H, J=8.5 Hz), 5.71 (q, 1H, J=6.8 Hz), 3.06 (s, 1H). ESHRMS m/z267.0271 (Calc'd for M−H 267.0269) Anal. Calc'd for C₁₃H₇F₃O₃+1.06% H₂O:C, 57.60; H, 2.72. Found C, 57.59; H. 2.62.

EXAMPLE 140

[1306]

[1307] 6-Methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1308] 4-Methylsalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 191.8-193.0° C. ¹HNMR (acetone-d₆/300 MHz) 7.80 (s, 1H), 7.72-7.73 (m, 2H), 6.90 (d, 1H,J=8.4 Hz), 5.91 (q, 1H, J=7.2 Hz). Anal. Calc'd for C₁₂H₉O₃F₃: C, 55.82;H, 3.51. Found: C, 55.89; H, 3.49.

EXAMPLE 141

[1309]

[1310]6-Chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[1311] The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: mp 194.0-196.0° C. ¹HNMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.34 (d,1H, J=2.4 Hz),7.21 (d, 1H, J=2.4 Hz), 6.99 (s, 1H), 6.96 (s, 1H), 5.69(q, 1H, J=6.7 Hz), 3.86 (s, 3H). FABLRMS m/z 402.2 (M+NH₄). ESHRMS m/z383.0267 (M−H, Calc'd. 383.029796). Anal. Calc'd. for C₁₈H₁₂ClF₃O₄: C,56.20; H, 3.14; Cl, 9.21. Found: C, 56.08; H, 3.11; Cl, 9.13.

EXAMPLE 142

[1312]

[1313]6-Chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylic acid

[1314] Step 1: Preparation of ethyl3-(5-chloro-2-hydroxyphenyl)-3-oxo-propionate

[1315] A solution of lithium hexamethyldisilazide (800 mL of 1.0 Msolution in THF, 800.0 mmol) was chilled to −78° C. under a nitrogenatmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g,266.67 mmol) in THF (130 mL) was added dropwise to the stirred solutionover 0.5 hour. The reaction was held at −78° C. for 1 hour, warmed to−10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to −78° C.Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringein one portion. The temperature was maintained at −78° C. for 0.5 hour,warmed to room temperature over 0.5 hour, and stirred for 3 hours. Thecrude reaction mixture was carefully poured over a mixture of rapidlystirred ice (1200 mL)/conc HCl (222 mL). The layers were separated andthe aqueous phase was extracted with ethyl acetate. The combined organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo yielding an oil that began to crystallize. Hexanes(150 mL) was added and crystallization proceeded. The crystallineproduct was collected by vacuum filtration to afford the title compound(29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1° C. ¹H NMR(CDCl₃/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98(d, 1H, J=8.9 Hz), 4.25 (q, 2 H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H,7.3 Hz). FABLRMS m/z 249 (M+Li) . EIHRMS m/z 242.0346 (M+, Calc'd242.0346). Anal. Calc'd for C₁₁H₁₁ClO₄: C, 54.45; H, 4.57. Found: C,54.48; H, 4.62.

[1316] Step 2. Preparation of ethyl2-(trifluoromethyl)-6-chloro-4-oxo-4H-1-benzopyran-3-carboxylate.

[1317] The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added totrifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassiumcarbonate (44 g, 318 mmol) and toluene (400 mL). This suspension wasstirred at room temperature for 36 hours, then heated to reflux for 4hours. After cooling to room temperature, the suspension was poured overrapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCl (12 N,50 mL). The resulting organic phase was separated from the clearmixture, was washed with water ( 5×500 mL), brine (1×500 mL), dried overMgSO₄, filtered and concentrated in vacuo yielding tan solid which wasdried under high vacuum. This sample was partially dissolved in heptane(100 mL) and ethyl acetate (12 mL) with heating on a steam bath, wasfiltered to remove insoluble material. The filtrate was allowed to coolto room temperature yielding the desired 4-oxo-4H-1-benzopyran as afluffy tan solid (14.17 g, 56%): mp 106.7-108.6° C. This material was ofsuitable purity to use in the next step without further purification.

[1318] Step 3. Preparation of ethyl2-(trifluoromethyl)-4-oxo-dihydro-1-benzopyran-3-carboxylate.

[1319] A stirred, chilled (0° C.) solution of the ketone (Step 2) (6.92g, 21.58 mmol) in tetrahydrofuran (40 mL) and ethanol (50 mL) wastreated portion-wise with sodium borohydride (NaBH₄, 0.41 g, 10.79mmol). After 3 h additional sodium borohydride (0.30 g, 7.93 mmol) wasadded portion-wise over 1 hour. The reaction was poured into rapidlystirred cold aqueous HCl (15 mL of 12 N HCl diluted to 300 mL). Duringthe addition a precipitate formed, that was collected by vacuumfiltration and dried under high vacuum yielding the desired substituted4-oxo-dihydro-1-benzopyran as a white powder (6.92 g, 99%): mp80.2-84.9° C. ¹H NMR (CDCl₃/300 MHz) 12.60 (br s, 1H), 7.69 (d, 1H,J=2.6 Hz), 7.34 (dd, 1H, J=2,6, 8.7 Hz), 6.93 (d, 1H, J=8.7 Hz), 5.59(q, 1H, 6.6 Hz), 4.46−4.23 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z329 (M+Li). EIHRMS m/z 322.0213 (M+, Calc'd 322.0220). Anal. Calc'd forCl₃H₁₀Cl₁F₃O, with 3.57% water: C, 46.67; H, 3.41. Found: C, 46.62; H,3.14.

[1320] Step 4. Preparation of ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1321] A 50 mL-Morton flask fitted with septa and addition funnel wascharged with 2,6-di-tert-butylpyridine (1.782 g, 8.679 mmol), methylenechloride (15 mL), and trifluoromethanesulfonic anhydride (1.22 mL, 2.04g, 7.23 mmol) followed by the dropwise addition of the chroman-4-one(Step 3)(2.145 g, 5.786 mmol) in methylene chloride (12 mL) over 0.33hour. After stirring for 16 h at room temperature, the reaction wasconcentrated in vacuo and diluted with diethyl ether (50 mL) yielding asuspension. The suspension was vacuum filtered and the filtrate washedwith cold 2 N HCl and brine, dried over MgSO4, filtered and concentratedin vacuo yielding the desired triflate as a light yellow powder (1.45 g,55%) of suitable purity to use without further purification: mp79.2-80.4° C. ¹H NMR (CDCl₃/300 MHz) 7.40 9s, 1H), 7.37 (d, 1H, J=2.4Hz), 7.02−6.99 (m, 1H), 5.92 (q, 1H, J=6.6 Hz), 4.47−4.32 (m, 2H), 1.39(t, 3H, J=7.2 Hz).

[1322] Step 5. Preparation of ethyl6-chloro-4-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1323] Ethyl6-chloro-4-trifluoromethanesulfoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Step 4) (1.50 g, 3.30 mmol) was dissolved in anhydrous THF (40 mL)in a100 mL round bottomed flask under nitrogen.Tetrakis(triphenylphosphine)palladium(0) (0.267 g, 0.231 mmol) andlithium chloride (0.140 g, 3.3 mmol) were added, followed bytributylethenylstannane (1.15 g, 3.6 mmol). The resulting solution washeated to reflux for 18 hours. GCMS analysis indicated the startingmaterial had been consumed. The reaction mixture was allowed to cool toroom temperature and was poured into 20% ammonium fluoride solution (50mL). After stirring for one hour, diethyl ether (100 mL) was added andthe mixture was washed with water (2×50 mL). The organic phase was driedover MgSO₄, filtered, and concentrated in vacuo yielding a brown oil.The crude material was purified by flash column chromatography (hexane)to afford the ester as a yellow oil, which crystallized upon standing(0.760 g, 69%): mp 51.9-53.2° C. ¹H NMR (CDCl₃/300 MHz) 7.46 (d, 1H,J=2.4 Hz), 7.28−7.14 (m, 2H), 6.96 (d, 1H, J=8.7 Hz), 5.77−5.71 (m, 2H),5.38 (dd, J=1.2, 17.9 Hz), 4.32−4.26 (m, 2H), 1.33 (t, 2H, J=7.1 Hz).FABLRMS m/z 333.2 (M+H). ESHRMS m/z 333.0510 (M+H, Calc'd.333.050532.Anal. Calc'd for C₁₅H₁₂ClF₃O₃ (1.14 wt % H₂O): C, 53.53; H, 3.72; Cl,10.53. Found: C, 53.46; H, 3.42; Cl, 10.70.

[1324] Step 6. Preparation of6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[1325] The ester from Step 5 (0.300 g, 0.902 mmol) was dissolved in aTHF-EtOH-H₂O mixture (10 mL, 7:2:1) and treated with sodium hydroxide(0.360 mL, 0.902 mmol of a 2.5 N solution). This solution was stirred atroom temperature for 18 hours. The solvent was evaporated and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL was addedand the mixture acidified by the addition of concentrated HCl. Theorganic layer was separated, and the aqueous phase was extracted withdiethyl ether (2×10 ml). The ether extracts were combined, dried overMgSO₄, filtered, and concentrated in vacuo yielding a yellow solid,which was recrystallized in diethyl ether-hexane to afford the titlecompound as a white solid (0.163 g, 59%): mp 143.0-145.0° C. 1H NMR(CDCl₃/300 MHz 7.49 (d, 1H, J=2.6 Hz), 7.33−7.17 (m, 2H), 6.99 (d, 1H,J=8.5 Hz), 5.82−5.72 (m, 2H), 5.42 (d, 1H, J=17.9 Hz). ESHRMS m/z303.00207 (M−H, Calc'd. 303.003582). Anal. Calc'd for C₁₃H₈ClF₃O₃ (1.10wt % H₂O): C, 50.69; H, 2.74; Cl, 11.51. Found: C, 50.57; H, 2.37; Cl,11.75.

EXAMPLE 143

[1326]

[1327]6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic acid

[1328] The 2H-1-benzopyran-3-carboxylic acid was prepared from ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 142, Step 4) using a procedure similar to that described inExample 142, Steps 5-6: mp 225.5-226.6° C. 1H NMR (DMSO-d₆/300 MHz).7.46−7.39 (m, 4H), 7.20−7.13 (m, 3H), 6.52 (d, 1H, J=2.42 Hz), 6.12(q,1H, J=7.1 Hz). FABLRMS m/z 355.1 (M+H). ESHRMS m/z 353.0215 (M−H,Calc'd. 353.019232). Anal. Calc'd. for C₁₇H₁₀ClF₃O₃: C. 57.56; H, 2.84;Cl, 10.17. Found: C, 57.18; H, 2.66; Cl, 10.17.

EXAMPLE 144

[1329]

[1330]6-Chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1331] The 2H-1-benzopyran-3-carboxylic acid was prepared from ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 142, Step 4) using a procedure similar to that described inExample 142, Steps 5-6: mp 200.8-206.7° C. ¹H NMR (CDCl₃/300 MHz)7.52(dd, 1H, J=1.21, 5.04 Hz), 7.28 (dd, 1H, J=2.42, 8.67 Hz), 7.15 (dd,1H, J=1.21, 3.42 Hz), 6.98−6.93 (m, 2H), 5.83 (q, 1H, J=20 6.9 Hz).FABLRMS m/z 378 (M+NH₄). Anal. Calc'd. for C₁₅H₈CIF₃O₃S: C, 49.94; H,2.24; Cl, 9.83; S, 8.89. Found: C, 50.02; H, 1.98; Cl, 9.34; S, 8.89.

EXAMPLE 145

[1332]

[1333] 6-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1334] Step 1. Preparation of 5-methyl-2-mercaptobenzaldehyde.

[1335] Tetramethylethylenediamine (TMEDA)(12.6 mL, 83.5 mmol) was addedvia syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and thesolution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. Theresulting tan slurry was stirred overnight at room temperature, chilledto 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over2 minutes. The resulting gummy slurry was stirred at room temperaturefor 1.3 hours. The reaction mixture was added to 3 N HCR (150 mL). Thismixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentrated invacuo yielding a brown oil. This oil was purified by flashchromatography over silica gel, eluting with 10% ethyl acetate-hexanesto afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intenselyyellow solid suitable for use without further purification.

[1336] Step 2. Preparation of ethyl6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate.

[1337] The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol)was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7mmol). With stirring, K₂CO₃ (3.78 g, 27.3 mmol) was added causing thereaction to become a deep red. The reaction was stirred at roomtemperature for 20 hours, acidified with 3N HCl, diluted with ethylacetate and washed with water, saturated NaHCO₃ solution, brine, driedover MgSO₄, filtered and concentrated in vacuo yielding an oil. The oilwas crystallized from diethyl ether-petroleum ether to give ethyl6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as alight yellow solid (4.47 g, 69%): mp 93.1-94.7° C. ¹H NMR(acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz),7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s,3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).

[1338] Step 3. Preparation of6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid.

[1339] The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5mL) and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL,3.8 mmol), and stirred at room temperature for 88 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl, filtered, andrecrystallized from diethyl ether/petroleum ether to yield the titlecompound as a yellow solid (0.14 g, 28%): mp 180.8-184.2° C. ¹H NMR(acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz),7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMSm/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'dfor C₁₂H₉F₃O₂S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.

EXAMPLE 146

[1340]

[1341] 6,8-Dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1342] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp 220-225° C.(dec). ¹H NMR (acetone-d6/300 MHz) 11.5 (brs, 1H), 7.94 (s, 1H), 7.26(s, 1H) 7.14 (s, 1H), 4.98 (q, 1H, J=8.7 Hz), 2.34 (s, 3H), 2.31 (s,3H). FABLRMS m/z 295 (M+Li). EIHRMS m/z 288.0431 (M+, Calc'd 288.0432).Anal. Calc'd for C₁₃H₁₁F₃O₂S: C, 54.16; H. 3.85. Found: C, 54.10; H,3.91.

EXAMPLE 147

[1343]

[1344]6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1345] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp183.8-184.6° C. ¹H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.68 (d, 1H,J=2.2 Hz), 7.46 (dd, 1H, J=8.3 Hz 2.2 Hz), 7.37 (d, 1H, J=8.3 Hz), 4.94(q, 1H, J=8.7 Hz), 1.34 (s, 9H). FABLRMS m/z 334 (M+NH₄). ESHRMS m/z334.1087 300 MHz) 7.52 (dd, 1H, J=1.21, 5.04 Hz), 7.28 (dd, 1H, J=2.42,8.67 Hz), 7.15 (dd, 1H, J=1.21, 3.42 Hz), 6.98−6.93 (m, 2H), 5.83 (q,1H, J=6.9 Hz). FABLRMS m/z 378 (M+NH₄). Anal. Calc'd. for C₁₅H₈ClF₃O₃S:C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C, 50.02; H, 1.98; Cl,9.34; S, 8.89. (M+NH₄, Calc'd 334.1089). Anal. Calc'd for C₁₅H₁₅F₃O₂S:C, 56.95; H, 4.78. Found: C, 57.03; H, 4.83.

EXAMPLE 148

[1346]

[1347] 7-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1348] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp186.6-191.9° C. ¹H NMR (acetone-d6/300 MHz) 7.96 (s, 1H), 7.49 (dd, 1H,J=7.6 Hz 2.82 Hz), 7.27 (s, 1H), 7.14 (d, 1H, J=7.6 Hz), 4.96 (q, 1H,J=5.3 Hz), 2.36 (s, 3H). ESHRMS m/z 273.0204 (M−H. Calc'd 273.0197).Anal. Calc'd for C₁₂H₉F₃O₂S (3.32 wt % H₂O): C, 50.81; H, 3.57. Found:C, 50.79; H, 3.44.

EXAMPLE 149

[1349]

[1350] 6,7-Dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1351] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp 235-237° C.¹H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H),4.91 (q, 1H, J=8.7 Hz), 2.28 (s, 3H), 2.26 (s, 3H). FABLRMS m/z 295(M+Li). EIHRMS m/z 288.0439 (M+, Calc'd 288.0432). Anal. Calc'd forC₁₃H₁₁F₃O₂S: C, 54.16; H, 3.85. Found: C, 54.13; H, 3.85.

EXAMPLE 150

[1352]

[1353] 8-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1354] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp 224-225° C.¹H NMR (acetone-d6/300 MHz) 11.60 (br s, 1H), 8.00 (s, 1H), 7.44 (d, 1H,J=6.7 Hz), 7.31 (d, 1H, J=6.8 Hz), 7.21 (m, 1H), 5.05 (q, 1H, J=8.5 Hz),2.38 (s, 3H). FABLRMS m/z 292 (M+NH₄). ESHRMS m/z 292.0591 (M+NH₄,Calc'd 292.0619). Anal. Calc'd for C₁₂H₉F₃O₂S: C, 52.55; H, 3.31. Found:C, 52.63; H, 3.38.

EXAMPLE 151

[1355]

[1356] 2-(Trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

[1357] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 145: mp 187-190° C.¹H NMR (acetone-d6/300 MHz) 8.01 (s, 1H), 7.60 (d, 1H, J=7.5 Hz), 7.45(m, 2H), 7.31 (m, 1H), 4.98 (q, 1H, J=8.7 Hz). ESHRMS m/z 259.0070 (M−H,Calc'd 259.0041). Anal. Calc'd for C₁₁H₇F₃O₂S: C, 50.77; H, 2.71. Found:C, 50.75; H, 2.78.

EXAMPLE 152

[1358]

[1359]6-Chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1360] Step 1. Preparation ofN,N-dimethyl-O-(4-chloro-2-formyl-5-methylphenyl)thiocarbamate.

[1361] A mixture of 5-chloro-4-methylsalicylaldehyde (12.96 g, 76.0mmol) and triethylamine (11.58 g, 114.4 mmol) was dissolved in anhydrousDMF (15 mL) treated with N,N-dimethylthiocarbamoyl chloride (11.25 g,91.0 mmol) and stirred at room temperature for 16 hours. The reactionwas treated with 3 N HCl (50 mL) and filtered to give an orange solid.The solid was dissolved in ethyl acetate washed with 3 N HCl, water,brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo toafford a brown solid (16.79 g) which was recrystallized from diethylether/hexane to give the O-aryl thiocarbamate as a tan solid (4.92 g,25%): ¹H NMR (acetone-d6/300 MHz) 9.96 (s, 1H), 7.80 (s, 1H), 7.19 (s,1H), 3.46 (s, 3H), 3.42 (s, 3H), 2.43 (s, 3H).

[1362] Step 2. Preparation ofN,N-dimethyl-S-(4-chloro-2-formyl-5-methylphenyl)thiocarbamate.

[1363] The O-aryl thiocarbamate (Step 1) (4.92 g, 19.1 mmol) wasdissolved in N,N-dimethylaniline (25 mL) and immersed in and stirred at200° C. for 1.5 hours. The reaction mixture was cooled to roomtemperature and poured into a mixture of 3 N HCl (200 mL) and ice.Filtration gave a brown semisolid which was dissolved in ethyl acetate,washed with 3 N HCl, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford the S-arylthiocarbamate as a brown oil(3.80 g, 77%) which was used in the next step without furtherpurification.

[1364] Step 3. Preparation of ethyl6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate.

[1365] The S-arylthiocarbamate (Step 2) (3.80 g, 14.7 mmol) wasdissolved in THF (10 mL) and ethanol (10 mL), treated with 2.5 N sodiumhydroxide (16.5 mL, 34.2 mmol), and stirred at room temperature for 0.9hours. The reaction was diluted with diethyl ether and washed with 3 NHCl, brine, dried over MgSO₄, filtered and concentrated in vacuo toyield the crude substituted 2-mercaptobenzaldehyde as a brown oil (2.82g). This oil was added to DMF (10 mL) and ethyl 4,4,4-trifluorocrotonate(3.89 g, 23.1 mmol). With stirring, K₂CO₃ (3.23 g, 23.4 mmol) was addedcausing the reaction to become a deep red. The reaction was stirred atroom temperature for 14.5 hours, acidified with 3 N HCl, extracted withethyl acetate. The resulting organic phase was washed with brine, driedover MgSO₄, filtered and concentrated in vacuo to give a yellow solid(6.36 g) which was used in the next step without further purification.

[1366] Step 4. Preparation of6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1367] The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10mL) and ethanol (10 mL), treated with 2.5 N sodium hydroxide (5.5 mL,13.8 mmol), and stirred at room temperature for 4.8 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl yielding asuspension. The solid was collected by filtration and was recrystallizedfrom ethanol-water to yield the title compound as a yellow solid (0.20g, 11%): mp 240.5-241.7° C. ¹H NMR (acetone-d6/300 MHz) 7.99 (s, 1H),7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J=8.5 Hz), 2.39 (s, 3H).FABLRMS m/z 307 (M−H). FABHRMS m/z 306.9831 (M−H, Calc'd 306.9807).Anal. Calc'd for C₁₂H₈ClF₃O₂S: C, 46.69; H, 2.61; Cl, 11.48. Found: C,46.78; H, 2.61; Cl, 11.41.

EXAMPLE 153

[1368]

[1369] 7-Chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1370] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 152: mp225.7-227.3° C. ¹H NMR (acetone-d6/300 MHz) 8.02 (s, 1H), 7.63 (d, 1H,J=8.3 Hz), 7.54 (d, 1H, J=2.0 Hz), 7.36 (dd, 1H, J=8.3 Hz 2.0 Hz), 5.04(q, 1H, J=8.5 Hz). ESHRMS m/z 292.9646 (M−H, Calc'd 292.9651).

EXAMPLE 154

[1371]

[1372] 6,7-Dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

[1373] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 152: mp262.5-263.5° C. ¹H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.90 (s, 1H),7.74 (s, 1H), 5.09 (q, 1H, J=8.5 Hz). ESHRMS m/z 326.9242 (M−H, Calc'd326.9261).

EXAMPLE 155

[1374]

[1375]2-(Trifluoromethyl)-6-[(trifluoromethyl)thiol-2H-1-benzothiopyran-3-carboxylicacid

[1376] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 152: mp129.3-132.4° C. ¹H NMR (acetone-d6/300 MHz) 8.10 (s, 2H), 8.00 (s, 2H),7.71 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=8.1 Hz), 5.09 (q, 1H, J=8.5 Hz).ESHRMS m/z 358.9630 (M−H, Calc'd 358.9635).

EXAMPLE 156

[1377]

[1378] 6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylicacid

[1379] The 2H-1-benzothiopyran-3-carboxylic acid was prepared by aprocedure similar to the method described in Example 152: mp217.9-220.3° C., ¹H NMR (acetone-d6/300 MHz) 12.50−11.20 (br s, 1Hexch.), 8.06 (s, 1H), 7.75 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=2.2 Hz),5.23 (q, 1H, J=8.5 Hz). ESLRMS m/z 327 (M−H). ESHRMS m/z 326.9272 (M−H,Calc'd 326.9261).

EXAMPLE 157

[1380]

[1381] 6-Chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1382] Step 1. Preparation of 2-amino-5-chlorobenzaldehyde.

[1383] 2-Amino-5-chlorobenzyl alcohol (4.8 g, 30 mmol) and activatedmanganese (IV) oxide (21 g, 240 mmol) were refluxed in chloroform (100mL) for 1 hour. The contents were allowed to cool, filtered throughdiatomaceous earth and concentrated in vacuo to afford the2-amino-5-chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74-76° C.¹H NMR (CDCl₃, 300 MHz) 9.80 (s, 1H), 7.42 (s, 1H), 7.23 (d, 1H, J=7.0Hz), 6.60 (d, 1H, J=7.0 Hz).

[1384] Step 2. Preparation of ethyl6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1385] The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol),anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrousdimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contentswere allowed to cool and partitioned between ethyl acetate (200 mL) andwater (200 mL). The aqueous layer was extracted with ethyl acetate(1×100 mL). The ethyl acetate extracts were combined and washed withbrine (1×200 mL), dried over MgSO₄, and concentrated in vacuo leaving adark oil which solidified upon standing. The solid was purified-by flashchromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractionscontaining the desired product were combined, concentrated in vacuo andthe residue recrystallized from ethyl acetate-hexanes to afford theethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate asa yellow solid (16.36 g, 56%): mp 132.6-134.2° C. ¹H NMR (CDCl₃, 300MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H,J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMSm/z 306.0468 (M+H⁺, Calc'd 306.0509). Anal. Calc'd for C₁₃H₁₁NO₂F₃Cl: C,51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.

[1386] Step 3. Preparation of6-chloro-1,2-dihydro-2-(trifluoro-methyl)-3-guinolinecarboxylic acid.

[1387] The ester from Step 2 (1.7 g, 5.6 mmol) and 2.5 N sodiumhydroxide (4.4 mL, 11 mmol) were mixed in tetrahydrofuran (25 mL),methanol (10 mL), and water (25 mL). After stirring overnight, contentswere concentrated in vacuo to remove the THF and methanol. The aqueoussolution remaining was extracted with diethyl ether (2×100 mL). Theresulting aqueous layer was acidified with 2 N HCl causing theprecipitation of an oil. The oil was purified by flash chromatography onsilica gel, eluting with ethyl acetate-hexanes (1:1). Fractionscontaining the desired product were combined, and concentrated in vacuo.The residue was triturated with dichloromethane, and filtered to affordthe 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acidas a yellow solid (0.645 g, 41%): mp 187.8-188.8° C. ¹H NMR (acetone-d₆,300 MHz) 7.69 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 6.83 (d,1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). ESHRMS m/z 276.0040 (M−H,Calc'd 276.0039). Anal. Calc'd for C₁₁H₇NO₂F₃Cl+2.6% H₂O: C, 46.39; H,2.98; N, 4.92. Found: C, 45.99; H, 2.54; N, 4.85.

EXAMPLE 158

[1388]

[1389]6,8-Dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

[1390] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 157: mp 223.4-225.7° C.¹H NMR (acetone-d₆, 300 MHz) 7.82 (s, 1H), 7.40 (m, 2H), 6.53 (brs, 1H),5.40 (m, 1M). ESHRMS m/z 309.9657 (M−H, Calc'd 309.9649). Anal. Calc'dfor C₁₁H₆NO₂F₃Cl₂: C, 42.34; H, 1.94; N, 4.49. Found: C, 42.20; H, 1.74;N, 4.52.

EXAMPLE 159

[1391]

[1392]6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

[1393] The 1,2-dihydro-3-quinolin carboxylic acid was pr pared by aprocedure similar to that described in Example 157: mp 186.6-188.9° C.¹H NMR (acetone-d₆, 300 MHz) 7.79 (s, 1H), 7.32 (m, 1H), 6.71 (m, 1H),6.64 (brs, 1H), 5.21 (m, 1H). ESHRMS m/z 278.0262 (M−H, Calc'd278.0240). Anal. Calc'd for C₁₁H₆NO₂F₅+1.58% H₂O: C, 46.58; H, 2.31; N,494. Found: C, 46.20; H, 2.07; N, 4.54.

EXAMPLE 160

[1394]

[1395] 6-Iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

[1396] Step 1. Preparation of ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1397] A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol),diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at60° C. for 8 hours. The solution was cooled to room temperature and thesolution poured into ethyl acetate-hexanes (1:1, 500 mL). The solutionwas extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturatedaqueous ammonium chloride (2×200 mL), dried over sodium sulfate,filtered and concentrated in vacuo. The resulting dark yellow oil wasdissolved in hexanes (100 mL) and fine yellow crystals formed uponstanding. Vacuum filtration of this suspension yielded ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fineyellow crystals (19.3 g, 50% yield): mp 137-138° C. ¹H NMR (CDCl₃, 300MHz) 7.62 (s, 1H), 7.36-7.48 (m, 2H), 6.43 (d, J=8.2 Hz), 5.36 (brs,1H), 5.11 (q, 1H, J=7.1 Hz), 4.25-4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).ESHRMS m/z 395.9716 (M−H, Calc'd 395.9708).

[1398] Step 2. Preparation of6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-guinolinecarboxylic acid

[1399] Hydrolysis of the ester (Step 1) was performed by a proceduresimilar to that described in Example 157, Step 3, yielding thecarboxylic acid. mp 188-192° C. ¹H NMR (CD₃OD/300 MHz) 7.668 (s, 1H),7.46 (d, 1H, J=2.2 Hz), 7.39 (dd, 1H, J=8.4, 2.2 Hz), 6.52 (d, 1H, J=8.4Hz), 5.01 (q, 1H, J=7.5 Hz). ESHRMS m/z 367.9401 (M, Calc'd 367.9395).

EXAMPLE 161

[1400]

[1401] 6-Bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1402] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 160: mp 185-186’ C. ¹HNMR (CD₃OD/300 MHz) 7.68 (s, 1H), 7.31 (d, 1H, J=2.2 Hz), 7.23 (dd, 1H,J=8.7, 2.2 Hz), 6.64 (d, 1H, J=8.7 Hz), 5.01 (q, 1H, J=7.5 Hz). EIHRMSm/z 319.9519 (M, Calc'd 319.9534). Anal. Calc'd for C₁₁H₇BrF₃NO₂: C,41.02; H, 2.19; N, 4.35; Found: C, 41.27, H, 2.23, N, 4.26.

EXAMPLE 162

[1403]

[1404]1,2-Dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1405] Step 1. Preparation of 2-amino-5-(trifluoromethoxy)benzoic acid.

[1406] 5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassiumhydroxide pellets (4 g) were mixed in water (35 mL) and cooled to 0° C.With vigorous stirring, a solution of 30% aqueous hydrogen peroxide(11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) wasadded drop-wise keeping the temperature below 10° C. After stirring 1hour at 0° C., glacial acetic acid (22 mL) was added drop-wise, causingfoaming and formation of a precipitate. The contents were stirredovernight and filtered to afford the 2-amino-5-trifluoromethoxybenzoicacid as an amber solid (12.5 g, 87%). A small amount was recrystallizedfrom ethyl acetate-hexanes to afford amber needles for an analyticalsample and the remaining compound was used without further purification:mp 142.5-144.2° C. ¹H NMR (CDCl₃, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H,J=8.0 Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd forC₈H₆NO₃F₃: C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N,6.35.

[1407] Step 2. Preparation of 2-amino-5-(trifluoromethoxy)benzylalcohol.

[1408] The 2-amino-5-trifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) intetrahydrofuran (20 mL) was added dropwise to borane methyl sulfidecomplex (1.5 mL, 15.0 mmol) in tetrahydrofuran (5 mL). The reaction wasrefluxed overnight and allowed to cool. A solution of 30% aqueoushydrogen peroxide (0.5 mL), 2.5 N sodium hydroxide (0.5 mL) and water(10 mL) was added drop-wise and the reaction stirred 0.5 hours. Afterdiluting with diethyl ether (50 mL), the organic layer was washed with0.1 M aqueous sodium meta-bisulfite (2×10 mL) and 2.5 N aqueous sodiumhydroxide (2×10 mL). The organic layer was diluted further with hexanes(50 mL) and washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,and concentrated in vacuo leaving an amber oil (1.9 g) which solidified.The solid was recrystallized from ethyl acetate-hexanes to afford the2-amino-5-trifluoromethoxybenzyl alcohol as a light amber solid (1.44 g,77%): mp 75.9-77.6° C. ¹H NMR (CDCl₃, 300 MHz) 7.00 (m, 2H), 6.65 (d,1H, J=8.0 Hz), 4.05 (s, 2H), 3.25 (brs, 3H). ESHRMS m/z 208.0592 (M+H⁺,Calc'd 208.0585). Anal. Calc'd for CH₈NO₂F₃: C, 46.39; H, 3.89; N, 6.76.Found: C, 46.61; H, 3.79; N, 6.71.

[1409] Step 3. Preparation of 2-amino-5-(trifluoromethoxy)-benzaldehyde.

[1410] The 2-amino-5-trifluoromethoxybenzyl alcohol from Step 2 (9.7 g,47 mmol) and manganese (IV) oxide (21 g, 240 mmol) were refluxed inchloroform (200 mL) for 1 hour. The contents were allowed to cool andfiltered. The filtrate was concentrated in vacuo leaving an amber oil(8.2 g) which solidified. The oil was distilled (bulb to bulb apparatus)at 50° C. (0.1 mm) to afford a yellow solid (7.2 g). The solid wasrecrystallized from hexanes to afford the desired2-amino-5-(trifluoromethoxy)-benzaldehyde as yellow crystals (4.4 g,46%): mp. 42-44° C. ¹H NMR (CDCl₃, 300 MHz) 9.81 (s, 1H), 7.36 (s, 1H),7.20 (d, 1H, J=9.0 Hz), 6.64 (d, 1H, J=9.0 Hz). EIHRMS m/z 205.0328 (M⁺,Calc'd 205.0350).

[1411] Step 4. Preparation of ethyl1,2-dihydro-6-(trifluoro-methoxy)-2(trifluoromethyl)-3-quinolinecarboxylate.

[1412] The 2-amino-5-(trifluoromethoxy)benzaldehyde from Step 3 (5.3 g,26 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol), and ethyl4,4,4-trifluorocrotonate (7.7 mL, 50 mmol) were mixed in anhydrousdimethylformamide (50 mL) and heated at 90° C. for 6 hours. The reactionwas allowed to cool to room temperature and was partitioned betweenethyl acetate (200 mL) and water (200 mL). The aqueous layer wasextracted with more ethyl acetate (100 mL). The ethyl acetate extractswere combined and washed with brine (200 mL), dried over MgSO₄, andconcentrated in vacuo yielding an oil (9.6 g). The oil was purified byflash chromatography on silica gel, eluting with ethyl acetate-hexanes(1:1). Fractions containing the desired product were combined,concentrated in vacuo, and the residue recrystallized from ethylacetate-hexanes to afford the ethyl1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylateas a yellow solid (4.05 g, 32%): mp. 123-125° C. ¹H NMR (CDCl₃, 300 MHz)7.65 (s, 1H), 7.02 (m, 2H), 6.60 (m, 1H), 5.10 (m, 1H), 4.60 (brs, 1H),4.28 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). ESHRMS m/z 356.0698 (M−H, Calc'd356.0721). Anal. Calc'd for C₁₄H₁₁NO₃F₆: C, 47.34; H, 3.12; N, 3.94.Found: C, 47.37; H, 3.04; N, 3.93.

[1413] Step 5. Preparation of1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid.

[1414] The ethyl1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylatefrom Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL)were mixed in methanol (15 mL) and water (15 mL). The solution washeated on a steam bath for 2 hours. The reaction was allowed to cool toroom temperature and was extracted with diethyl ether (50 mL). Theaqueous layer was acidified (pH=1) with 3 N HCl and extracted with ethylacetate (2×50 mL). The combined ethyl acetate extracts were dried overMgSO₄ and concentrated in vacuo leaving an oil. The oil was crystallizedfrom cold dichloromethane-hexanes to afford the1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylicacid as yellow needles (0.727 g, 89%): mp 127.7-128.9° C. ¹H NMR (CDCl₃,300 MHz) 7.80 (s, 1H), 7.05 (m, 2H), 6.62 (d, 1H, J=8.0 Hz), 5.13 (m,1H), 4.62 (brs, 1H). ESHRMS m/z 326.0252 (M−H, Calc'd 326.0252). Anal.Calc'd for C₁₂H₇NO₃F₆: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H,2.04; N, 4.24.

EXAMPLE 163

[1415]

[1416]6-(Trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1417] Step 1. Preparation ofN-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide.

[1418] A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride(32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° Cunder a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273mmol) was added drop-wise over 2 hours, maintaining the temperaturebelow 10° C. After the addition, the contents were allowed to warm toroom temperature for 2 hours. The reaction was washed with water (2×200mL), saturated ammonium chloride solution (2×200 mL), dried over sodiumsulfate and filtered. The solvent was removed in vacuo to afford a whitesolid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g,98%): mp 157-159° C. ¹H NMR (CDCl₃/300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H⁺, Calc'd246.1106). Anal. Calc'd for C₁₂H₁₁F₃NO: C, 58.77; H, 5.75; N, 5.71.Found: C, 58.28; H, 5.79; N, 5.65.

[1419] Step 2. Preparation of N-[2-formyl-4-(trifluoromethyl)phenyl]-2,2-dimethyl propanamide.

[1420] A 1 liter three neck round bottom flask equipped with equalizingaddition funnel, magnetic stirer and temperature monitoring device wascharged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction waschilled to −78° C. under nitrogen followed by slow addition ofn-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, suchthat the temperature of the reaction did not rise above −65° C. Thecontents were held at −78° C. for one hour, O° C. for two hours, thenchilled back to −78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol)was added. The contents were warmed to room temperature and stirred fortwo hours. Aqueous 1 N HCl was added to the reaction until the pHreached 1. The reaction was washed with water (2×200 mL), saturatedammonium chloride solution (2×200 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to afford a yellowsolid. The product was purified by flash chromatography (silica gel, 10%ethyl acetate, 90% hexanes) to yield, upon concentration of theappropriate fractions,N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid(7.36 g, 65%): mp 69-73° C. ¹H NMR (CDCl₃/300 MHz) 11.5 (br s, 1H), 9.99(s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,),1.37 (s, 9H). ESHRMS m/z 274.1060 (M +H⁺, Calc'd 274.1055). Anal. Calc'dfor C₁₃H₁₄F₃NO₂: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43;N, 5.01.

[1421] Step 3. Preparation of ethyl6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1422] To a suspension ofN-(2-formyl-4-(trifluoro-methylphenyl)-2,2-dimethyl propanamide (Step 2)(921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethylsulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8mmol) and the contents warmed to 30° C. for 4 hours. After the additionof ethyl acetate (50 mL), the reaction was washed with water (2×30 mL),saturated ammonium chloride solution (2×30 mL), dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuo to afford ayellow solid. The product was purified by flash chromatography (silicagel, eluant: ethyl acetate-hexanes, 1:9) to yield, upon concentration ofthe appropriate fractions, ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylateas a yellow solid (65 mg, 5%): mp 138-139° C. ¹H NMR (CDCl₃/300 MHz)7.67 (s, 1H), 7.26 (S, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H,), 5.14(m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMSm/z 338.0592 (M−H, Calc'd 338.0616). Anal. Calc'd for C₁₃H₁₁F₃NO₂: C,49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93.

[1423] Step 4. Preparation of ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-guinolinecarboxylicacid.

[1424] Ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylatefrom Step 3 (45 mg, 0.13 mmol) was suspended inmethanol-tetrahydrofuran-water (10 mL, 7:2:1). Lithium hydroxide (24 mg,0.52 mmol) was added, and the mixture was gently heated to reflux fortwo hours. The reaction was cooled to room temperature and 1 N HCl addeduntil pH=1. The organic solvent was removed in vacuo to afford asuspension of a crude yellow solid. Diethyl ether (20 mL) was added, andthe solution was washed with water (2×20 mL), saturated ammonium sulfate(2×20 mL), dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to yield6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid as a yellow solid, (0.041 g, 0.132 mmol, 99%): mp 150-156° C. ¹HNMR (CD₃OD/300 MHz) 7.78 (s, 1H), 7.48 (s, 1H), 7.40 (m, 1H), 6.81 (m,1H), 5.17 (m, 1H). ESHRMS m/z 310.0307 (M−H, Calc'd 310.0303).

EXAMPLE 164

[1425]

[1426] 6-Cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1427] Step 1. Preparation of ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1428] N,N-Dimethylformamide (5 mL) was degassed with nitrogen forthirty minutes in a three neck round bottom flask equipped with acondenser, temperature monitoring, nitrogen purge and heating mantle.Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate(Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792mmol) were added to the N,N-dimethylformamide and stirred vigorously forten minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53mmol) was added and the contents gently warmed to 80° C. for 2 hoursunder a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followedby extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfateand solvent removed in vacuo to yield a yellow solid. The product waspurified by flash chromatography (silica gel, ethyl acetate-hexanes,3:1) to yield, upon concentration of the appropriate fractions, ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as ayellow solid (188 mg, 48%): mp 211-212° C. ¹H NMR (CDCl₃/300 MHz) 7.68(s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s,1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH₄ ⁺,Calc'd 314.1116). Anal. Calc'd for C₁₄H₁₁F₃N₂O₂: C, 56.76; H. 3.74; N,9.46. Found: C, 56.44; H, 4.03; N, 9.29.

[1429] Step 2. Preparation of6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-guinolinecarboxylic acid.

[1430] To a suspension of ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (140 mg,0.45 mmol) in methanol-tetrahydrofuran-water (10 mL, 7:2:1) was addedlithium hydroxide (76 mg, 0.91 mmol) and the mixture gently heated toreflux for two hours. The contents were cooled to room temperature and 1N aqueous hydrochloric acid added until pH=1. The organic solvent wasremoved in vacuo to afford a suspension of crude yellow solid. Diethylether (20 mL) was added, and the solution was washed with water (2×20mL), saturated ammonium sulfate (2×20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to yield6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as ayellow solid, (116 mg, 95%): mp 238-240° C. ¹H NMR (CD₃OD/300 MHz) 7.75(s, 1H), 7.56 (m, 1H), 7.43 (m, 1H), 6.79 (d, 1H, J=8.5 Hz) 5.19 (q, 1H,J=7.1 Hz). EIHRMS m/z 267.0405 (M−H, Calc'd 267.0381). Anal. Calc'd forC₁₄H₁₁F₃N₂O₂: C, 53.74; H, 2.63; N, 10.45. Found: C, 53.99; H, 2.89; N,10.19.

EXAMPLE 165

[1431]

[1432]6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1433] Step 1. Preparation of ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1434] Ethyl6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example157, Step 2) (1.28 g, 4.21 mmol), tetrabutylammonium iodide (0.36 g,0.92 mmol) and aqueous NaOH (50%, 2 mL) were stirred vigorously inmethylene chloride (40 mL). Dimethyl sulfate (2.12 g, 16.84 mmol) wasadded to the dark orange mixture via syringe over 2 hours. Hexane (5 mL)was added, and the solution was washed with water (2×20 mL), saturatedammonium chloride solution (2×20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to afford the crudeester as a yellow solid. The solid was purified by flash chromatography(silica gel, 50 g; ethyl acetate-hexanes, 1:19) to yield, uponconcentration of the appropriate fractions, ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylate(1.2 g, 90% yield): mp 118-120° C. ¹H NMR (CD₃OD/300 MHz) 7.71 (s, 1H),7.30−7.26 (m, 2H), 6.77−6.74 (m, 1H), 5.12 (q, 1H, J=6.8 Hz), 4.44−4.22(m, 2H), 3.18 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). EIHRMS m/z 320.0701 (M−H,Calc'd 320.0665) Anal. Calc'd for C₁₄H₁₃F₃NO₂Cl: C, 52.60; H, 4.10; N,4.38. Found: C, 52.57; H, 4.14; N, 4.32.

[1435] Step 2. Preparation of6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1436] Ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoro-methyl)-3-quinolinecarboxylate(1.21g, 3.78 mmol) was suspended in methanol-tetrahyrofuran-water (20 mL,7:2:1). Lithium hydroxide (0.262 g, 6.24 mmol) was added, and themixture was gently heated to reflux for two hours. The reaction wascooled to room temperature and 1 N HCl added until pH=1. The organicsolvent was removed in vacuo to afford a suspension of crude yellowsolid. Diethyl ether (20 mL) was added, and the resulting solution waswashed with water (2×20 mL), saturated ammonium chloride (2×20 mL),dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to afford the product as a yellow solid,6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylicacid. (1.08 g, 98% yield): mp 208-209° C. ¹H NMR (CD₃OD/300 MHz) 7.69(d, 1H, J=2.5 Hz), 7.28−7.24 (m, 2H), 6.73 (dd, 1H, J=9.5, 2.5 Hz), 5.13(q, 1H, J=7.0), 3.16 (s, 3H). Anal. Calc'd for C₁₂H₉F₃NO₂Cl: C, 49.42;H, 3.11; N, 4.80; Cl, 12.16. Found: C, 49.88; H, 3.29; N, 4.59; Cl,12.42

EXAMPLE 166

[1437]

[1438]6-Chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid

[1439] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 229-231° C. ¹HNMR (CD₃OD/300 MHz) 7.77 (s, 1H), 7.58 (d, 2H, J=8.0 Hz), 7.39 (d, 2H,J=8.0 Hz), 7.30 (d, 1H, J=2.4), 7.13 (dd, 1H, J=8.9, 2.4 Hz), 6.75 (d,1H, J=8.9 Hz), 5.27 (q, 1H, J=7.0 Hz), 4.90 (ab, 2H, J=16.7 Hz, Δν=95.2Hz). EIHRMS m/z 434.0401 (Calc'd for M−H 434.0383) Anal. Calc'd forC₁₉H₁₄F₆NO₂Cl: C, 52.13; H, 3.22; N, 3.22; Found: C, 52.36; H, 2.91; N,3.21.

EXAMPLE 167

[1440]

[1441]6-Chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1442] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 250-253° C. ¹HNMR (CD₃OD/300 MHz) 7.74 (s, 1H), 7.32−7.13 (m, 6H), 6.76 (d, 1H, J=8.7Hz), 5.22 (q, 1H, J=7.0 Hz), 4.81 (ab, 2H, J=16.3 Hz, Δν=54.7 Hz).ESHRMS m/z 400.0105 (M−H, Calc'd 400.0119).

EXAMPLE 168

[1443]

[1444]6-Chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid

[1445] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 196-197° C. ¹HNMR (CD₃OD/300 MHz) 7.71 (s, 1H), 7.27−7.26 (m, 1H), 7.18−7.12 (m, 3H),6.85−6.81 (m, 3H), 5.16 (q, 1H, J=7.1 Hz), 4.69 (ab, 2H, J=15.3 Hz,Δν=111.8 Hz), 3.73 (s, 3H). ESHRMS m/z 396.0625 (M−H, Calc'd 396.0614).Anal. Calc'd for C₁₉H₁₄F₆NO₂Cl: C, 52.13; H, 3.22; N, 3.22. Found: C,52.36; H, 2.91; N, 3.21.

EXAMPLE 169

[1446]

[1447]6-Chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1448] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 258-260° C. ¹HNMR (CD₃OD/300 MHz) 7.78 (s, 1H), 7.66 (d, 2H, J=8.2 Hz), 7.41 (d, 2H,J=8.2 Hz), 7.33 (d, 1H, J=2.7 Hz), 7.15 (dd, 1H, J=8.7, 2.7 Hz), 6.71(d, 1H, J=8.7 Hz), 5.31 (q, 1H, J=7.0 Hz), 4.94 (ab, 2H, J=17.1, Δν=91.8Hz). ESHRMS m/z 391.0443 (M−H, Calc'd 391.0461). Anal. Calc'd forC₁₉H₁₂F₃N₂O₂Cl+0.53% H₂O: C, 57.79; H, 3.55; N, 7.09; Found: C, 57.26;H, 3.17; N, 6.78.

EXAMPLE 170

[1449]

[1450]6-Chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1451] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 225-228° C. ¹HNMR (CD₃OD-3% TFA/300 MHz) 8.14 (d, 2H, J=8.8 Hz), 7.77 (s, 1H), 7.42(d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=8.9, 2.4 Hz),6.67 (d, 1H, J=8.9 Hz), 5.27 (q, 1H, J=6.8 Hz), 4.93 (ab, 2H, J=17.2 Hz,Δν=95.0 Hz). ESHRMS m/z 411.0327 (M−H, Calc'd 411.0359).

EXAMPLE 171

[1452]

[1453]6-Chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1454] The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by aprocedure similar to that described in Example 165: mp 201-202° C. ¹HNMR (CD₃OD/300 MHz) 7.67 (s, 1H), 7.25−7.22 (m, 2H), 6.86 (d, 1H, J=8.7Hz), 5.21 (q, 1H, J=7.0 Hz), 3.81−3.71 (m, 1H), 3.47−3.39 (m, 1H), 1.20(t, 3H, J=7.2 Hz). ESHRMS m/z 304.0360 (M−H, Calc'd 304.0352).

EXAMPLE 172

[1455]

[1456](S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

[1457] To a solution of6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid(Example 157) (6.75 g, 24.3 mmol) in ethyl acetate (25 mL) was added(S)-(−)-α-methylbenzylamine (1.50 g, 12.2 mmol). To the resultingsolution was added hexanes (50 mL) with mixing. Stirring wasdiscontinued and the reaction held static at room temperature for 16hours during which time yellow crystals formed. The crystals werecollected and washed with ethyl acetate-hexanes (100 mL, 1:2). Theresulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL)and extracted with 1 N HCl (3×10 mL). The organic layer was dried oversodium sulfate and solvent removed at reduced pressure. The(s)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acidwas obtained as a yellow solid (648 mg, 10% yield). mp 173-176° C. ¹HNMR (acetone-d₆, 300 MHz) 7.80 (s, 1H), 7.35 (d, 1H, J=2.2 Hz), 7.18 (d,1H, J=8.0, J=2.2 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m,1H). Anal. Calc'd. for C₁₁H₇NO₂F₃Cl C, 47.40 H, 2.54; N, 5.40. Found C,47.49; H, 2.60; N, 4.98. The compound was determined to have an opticalpurity greater than 90% ee. Optical purity was determined by HPLC asdescribed in Example 66.

EXAMPLE 173

[1458]

[1459]6-(2,2,2-Trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1460] Step 1. Preparation of ethyl6-(1-hydroxy-2,2,2-trifluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1461] The aldehyde (Example 75, Step 1) (0.89 g, 3.0 mmol) was cooledto 0° C. and treated with a 0.5 M solution oftrimethyl(trifluoromethyl)silane (8.4 mL, 4.2 mmol) and four drops of a1.0 M solution of tetrabutylammonium fluoride was added. The reactionwas allowed to warm to room temperature and stirred for 21.1 hours. Thereaction was quenched with 3 N HCl, extracted with ethyl acetate, washedwith water, brine, dried over MgSO₄, and concentrated in vacuo to give abrown oil (1.02 g). This oil was purified by flash chromatography oversilica gel, eluting with 10% ethyl acetate/hexanes to afford a brown oil(0.77 g, 58%): ¹H NMR (CDCl₃/300 MHz) 7.72 (d, 1H, J=3.4 Hz), 7.34 (m,2H), 6.99 (d, 1H, J=8.5 Hz), 5.71 (q, 1H, J=6.8 Hz), 4.83 (q, 1H, J=6.4Hz), 4.33 (m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.11 (s, 9H). FABLRMS m/z 443(M+H).

[1462] Step 2. Preparation of6-(1-hydroxy-2,2,2-trifluoroethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

[1463] The ester from Step 1 (0.15g 0.34 mmol) was dissolved in THF (2mL) and ethanol (2 mL), treated with 2.5 N NaOH (1 mL, 2.5 mmol), andstirred at room temperature for 18.6 hours. The reaction mixture wasconcentrated in vacuo, acidified with 3 N HCl, extracted with ethylacetate, washed with 3 N HCl, brine, dried over MgSO₄, and concentratedin vacuo to give a yellow oil which was recrystallized from ethylacetate/hexane to yield a white solid (0.03 g, 25%): mp 114-120° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.65 (s, 1H), 7.60 (dd, 1H, J=8.2Hz 2.0 Hz), 7.11 (d, 1H, J=8.3 Hz), 5.87 (q, 1H, J=7.0 Hz), 5.24 (q, 1H,J=7.0 Hz). FABLRMS m/z 341 (M−H). ESHRMS m/z 341.0241 (M−H, Calc'd341.0249).

EXAMPLE 174

[1464]

[1465]6-Chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid

[1466] Step 1. Preparation ofN-[5-chloropyridin-2-yl]-2,2-dimethylpropanamide.

[1467] To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) andtriethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0°C, was added dropwise trimethylacetyl chloride in methylene chloride (15mL). The reaction was allowed to warm to room temperature while stirringovernight. The resulting mixture was washed with water, brine, and wasdried over MgSO₄ and filtered. Concentration of the filtrate in vacuoprovided a colorless oil (19.2 g). The oil was dissolved in hexanes andcooled causing the precipitation of a solid. The solid was collected byfiltration affording the amide as a white solid (14.96 g, 90%): mp51.4-53.4° C. ¹H NMR (CDCl₃/300 MHz) 8.25−8.15 (m, 2H), 8.00 (br s, 1H),7.68−7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd for C₁₀H₁₃N₂OCl: C, 56.47;H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.

[1468] Step 2. Preparation ofN-[5-chloro-3-formylpyridin-2-yl]-2,2-dimethylpropanamide.

[1469] To a chilled (−78° C.), stirred solution of the amide (Step 1)(5.0 g, 0.024 mole) in tetrahydrofuran (100 mL) was added t-butyllithium (1.7M in pentane, 32.4 mL, 0.055 mole) dropwise.Dimethylformamide (2.3 mL, 0.03 mole) was added dropwise at −78° C. over3 hours and the mixture allowed to warm room temperature. The reactionwas quenched with ice water (200 mL) and extracted with ethyl acetate.The resulting organic phase was dried over MgSO₄ and was concentrated invacuo to a volume of 20 mL. A white solid precipitated which wascollected by filtration yielding the formylated product (3.24 g, 56%):mp 168.7-170.8° C. ¹H NMR (CDCl₃/300 MHz) 10.60 (br s, 1H), 9.88 (s,1H), 8.57 (s, 1H), 8.00 (s, 1H), 1.28 (s, 9H). Anal. Calc'd forC₁₁H₁₃N₂O₂Cl: C, 54.89; H, 5.44; N, 11.64 Found: C, 54.87; H, 5.42; N,11.40.

[1470] Step 3. Preparation 2-amino-5-chloro-3-formylpyridine.

[1471] The product of Step 2 (2.7 g, 11 mmol) and 3 N HCl (50 mL) wereheated at reflux for 2 hours. The reaction was allowed to cool to roomtemperature and was concentrated in vacuo yielding a light yellow solid(2.1 g). The solid was partitioned between ethyl acetate and 2.5 N NaOHsolution. The ethyl acetate layer was dried over MgSO₄ and concentratedin vacuo providing a solid (1.7 g). The solid was recrystallized fromethyl acetate to give the desired substituted pyridine as yellow needles(1.2 g, 68%): mp 176.1-177.3° C. ¹H NMR (CDCl₃/300 MHz) 9.80 (s, 1H),8.21 (s, 1H), 7.75 (s, 1H), 6.75 (br s, 2H). Anal. Calc'd for C₆H₅N₂OCl:C, 46.03; H, 3.22; N, 17.89 Found: C, 45.90; H, 3.24; N, 17.80.

[1472] Step 4. Preparation of ethyl6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylate.

[1473] The substituted pyridine from Step 3 (1.7 g, 11 mmol), anhydrouspotassium carbonate (3.0 g, 22 mmol), and ethyl 4,4,4-trifluorocrotonate(3.3 mL, 22 mmol) were mixed in anhydrous dimethylformamide (20 mL) andheated at 80° C. for 2 hours. The reaction was allowed to cool to roomtemperature and was partitioned between ethyl acetate (100 mL) and water(100 mL). The aqueous layer was extracted with more ethyl acetate (100mL). The combined organic extracts were washed with brine (100 mL),dried over MgSO₄, and concentrated in vacuo yielding a waxy amber solidThe solid was triturated with diethyl ether providing the ester as ayellow solid (613 mg, 18%). A small amount was recrystallized from ethylacetate for analytical data: mp 180.1-181.9° C. ¹H NMR (CDCl₃/300 MHz)7.99 (s, 1H), 7.61 (s, 1H), 7.39 (s, 1H), 6.00 (br s, 1H), 5.33−5.20 (m,1H), 4.40−4.23 (m, 2H), 1.40−1.30 (m, 3H). Anal. Calc'd forC₁₂H₁₀N₂O₂F₃Cl: C, 47.00; H, 3.29; N, 9.13 Found: C, 46.83; H, 3.03; N,9.18.

[1474] Step 5. Preparation of6-chloro-2-(trifluoromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid.

[1475] The ester from Step 4 (1.3 g, 4.4 mmol) and 2.5 N sodiumhydroxide solution (3.5 mL, 9 mmol) were mixed in tetrahydrofuran (25mL), methanol (10 mL), and water (25 mL). The mixture was heated at 50°C. for 4 hours, allowed to cool to room temperature, and wasconcentrated in vacuo to remove the tetrahydrofuran and methanol. Theresulting aqueous solution was washed with diethyl ether (2×100 mL). Theaqueous phase was acidified with 3 N HCl causing the precipitation of ayellow solid (1.1 g). The solid was triturated with ethanol-acetone andcollected by vacuum filtration providing the title compound as a yellowsolid (276 mg, 23%): mp 287.4-288.4° C. ¹H NMR (acetone-d6/300 MHz)11.50 (br s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s,1H), 5.42−5.30 (m, 1H). Anal. Calc'd for C₁₀H₆N₂O₂F₃Cl: C, 43.11; H,2.17; N, 10.05 Found: C, 42.88; H, 2.03; N, 10.06.

EXAMPLE 175

[1476]

[1477] (S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1478] 6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid (Example 32) (300 g, 1.04 mol) was added to ethyl acetate (750 mL).The mixture was stirred for 5 minutes, warmed to 70° C. and held at thistemperature for 5 minutes. The resulting solution was cooled to 50° C.and (s)-(−)-α-methylbenzylamine (58 g, 0.48 mol)was added. Heptane (1880mL) was added and the mixture stirred for 0.5 hour, then stirring wasdiscontinued. The reaction was allowed to cool to 22° C. and stand for 8hours. The salt crystallized during this time and was collected byvacuum filtration. The solid was washed with ethyl acetate-heptane (1:3,2×50 mL). The solid obtained was dried at 40° C. under vacuum (20 mm)for 24 hours to give the salt (35 g, 16%).

[1479] A three-neck 2 L round bottom flask was purged with nitrogen andwas charged with deionized water (750 mL) and the salt (103 g, 0.24mole; This material was obtained using a similar procedure to thatdescribed above). To the resulting stirred suspension was addedconcentrated HCl (37 mL) drop-wise over 0.5 hours with good stirringbelow 20° C. causing the free carboxylic acid to precipitate. Afterstirring for 2 hours, the suspension was vacuum filtered and the solidwashed with deionized water (5×50 mL; until the washings were neutral).The solid was dried at 40° C. under vacuum (20 mm) for 12 hours yieldingthe title compound as a solid (74 g, 100%): mp 166.0-168.4° C. 1H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.60 (s, 2H), 6.04 (q, 1H, J=6.8 Hz).ESHRMS m/z 310.9489 (M−H, Calc'd 310.9450). This compound was determinedto have an optical purity of greater than 90% ee. The optical purity wasdetermined by the method described in Example 66.

EXAMPLE 176

[1480]

[1481] 7-Phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1482] 3-Phenoxyphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 180.0-181.0° C. ¹HNMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.47 (m, 3H), 7.26 (dt, 1H, J=7.6Hz, 1.4 Hz), 7.15 (d, 2H, J=7.7 Hz), 6.68 (dd, 1H, J=8.5 Hz 2.3 Hz),6.58 (s, 1H), 5.81 (q, 1H, J=7.1 Hz). 19F NMR (acetone-d₆/282 MHz) −79.5(d, J=7.2 Hz). FABLRMS m/z 335 (M−H). ESHRMS m/z 335.0542 (M−H, Calc'd335.0531). Anal. Calc'd for C₁₇H₁₁F₃O₄: C, 60.72; H, 3.30. Found: C,60.55; H, 3.29.

EXAMPLE 177

[1483]

[1484]6-Chloro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1485] 3-Phenoxyphenol was converted to the title compound by aprocedure similar to that described in Example 100: mp 220.2-221.8° C.¹H NMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.72 (s, 1H), 7.50 (m, 2H),7.28 (t, 1H, J=7.5 Hz), 7.15 (d, 2H, J=7.7 Hz), 6.53 (s, 1H), 5.81 (q,1H, J=7.1 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMSm/z 369 (M−H). ESHRMS m/z 369.0157 (M−H, Calc'd 369.0141). Anal. Calc'dfor C₁₇H₁₀ClF₃O₄: C, 55.08; H, 2.72; Cl, 9.56. Found: C, 54.94; H, 2.60;Cl, 9.84.

EXAMPLE 178

[1486]

[1487]6-Chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1488] Step 1. Preparation of methyl 3-methoxyphenylacetate.

[1489] Trimethylsilyl chloride (182 g, 1.68 mol) was added dropwise to asolution of 3-methoxyphenylacetic acid (127 g, 0.77 mol) in methanol(1.0 L) over 1.1 hours. The reaction was stirred at room temperature for17.25 hours, concentrated in vacuo, dissolved in ethyl acetate, driedover MgSO₄, and concentrated in vacuo, to give a brown oil (133 g, 97%):¹H NMR (CDCl₃/300 MHz) 7.24 (t, 1H, J=7.5 Hz), 6.83 (m, 3H), 3.80 (s,3H), 3.69 (s, 3H), 3.60 (s, 2H).

[1490] Step 2. Preparation of methyl2-(3-methoxyphenyl)-2-methylpropionate.

[1491] A 2L flask was charged with a 60% dispersion of sodium hydride inmineral oil (48.7 g, 1.22 mol) and THF (0.4 L). A solution of the esterfrom Step 1 (73.2 g, 0.41 mol) in THF (0.2 L) was added over one hourand the reaction was stirred for an additional 2.67 hours. The reactionwas cooled in ice and treated with methyl iodide (136.8 g, 0.96 mol)over a period of 0.67 hours, and then stirred at room temperature for14.75 hours. The reaction was poured into a mixture of 3N HCl (0. 3 L)and ice (0.8 L), extracted with ethyl acetate (0.8 L), washed with 10%NaHSO₃, water, brine, dried over MgSO₄ and concentrated in vacuo, togive a brown oil which was distilled under vacuum (2.2 mm Hg, 97-112°C.) to give a clear oil (50.9 g, 60%): ¹H NMR (CDCl₃/300 MHz) 7.25 (t,1H, J=8.0 Hz), 6.89 (m, 2H), 6.81 (dd, 1H, J=8.0 Hz, 2.6 Hz), 3.81 (s,3H), 3.66 (s, 3H), 1.57 (s, 6H).

[1492] Step 3. Preparation of methyl2-(3-hydroxyphenyl)-2-methylpropionate.

[1493] The ester from Step 2 (29.1 g, 140 mmol) was dissolved in CH₂Cl₂(170 mL) and cooled to −65° C. The reaction was treated with a 1.0 Msolution of boron tribromide in CH₂Cl₂ (180 mL, 180 mmol). The reactionwas stirred at −65° C. for 1.6 hours, then the cooling bath was removedand the reaction was warmed to room temperature. The reaction was addedto ice water and the layers were separated. The organic layer wasconcentrated in vacuo, dissolved in ethyl acetate, washed with saturatedNaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo, to givemethyl 2-(3-hydroxyphenyl)-2-methylpropionate as a brown oil (10.6 g,42%): ¹H NMR (CDCl₃/300 MHz) 7.19 (m, 1H), 6.90 (d, 1H, J=7.9 Hz), 6.84(m, 1H), 6.75 (d, 1H, J=8.1 Hz), 3.66 (s, 3H), 1.56 (s, 6H). Thesaturated NaHCO₃ layer was acidified with concentrated HCl, extractedwith ethyl acetate washed with the, dried over MgSO₄ and concentrated invacuo, to give 2-(3-hydroxyphenyl)-2-methylpropionic acid as a brown oil(15.8 g, 42%): ¹H NMR (CDCl₃/300 MHz) 7.20 (m, 1H), 6.97 (dd, 1H, J=7.9Hz, 0.8 Hz), 6.88 (m, 1H), 6.75 (dd, 1H, J=8.1 Hz, 0.8 Hz), 1.57 (s,6H).

[1494] Step 4. Preparation of 2-(3-hydroxyphenyl)-2-methylpropionicacid.

[1495] The ester (Step 3) was hydrolyzed to the carboxylic acid via amethod similar to that described in Example 1, Step 2: ¹H NMR (CDCl₃/300MHz) 7.20 (m, 1H), 6.97 (dd, 1H, J=7.9 Hz, 0.8 Hz), 6.88 (m, 1H), 6.75(dd, 1H, J=8.1 Hz, 0.8 Hz), 1.57 (s, 6H).

[1496] Step 5. Preparation of 3-(2-hydroxy-1,1-dimethylethyl)phenol.

[1497] The carboxylic acid obtained from several lots obtained from Step3 and Step 4 (31.6 g, 175 mmol) was dissolved in THF (150 mL), cooled to0° C., and treated with borane methyl sulfide complex (33 mL, 348 mmol).The reaction was warmed to room temperature and stirred for 7.5 hours.The reaction was added to 3N HCl, extracted with ethyl acetate, washedwith brine, dried over MgSO₄ and concentrated in vacuo, to give a brownoil (18.6 g, 64%): ¹H NMR (CDCl₃/300 MHz) 7.21 (m, 1H), 6.96 (d, 1H,J=7.9 Hz), 6.86 (t, 1H, J=2.0 Hz), 6.71 (dd, 1H, J=7.8 Hz, 2.4 Hz), 3.60(s, 2H), 1.31 (s, 6H).

[1498] Step 6. Preparation of4-(2-hydroxy-1,1-dimethylethyl)salicylaldehyde.

[1499] The phenol (Step 5) was converted to the salicylaldehyde via amethod similar to that described in Example 2, Step 1: mp 80.4-81.9° C.¹H NMR (CDCl₃/300 MHz) 11.00 (s, 1H), 9.87 (s, 1H), 7.51 (d, 1H, J=8.3Hz), 7.08 (dd, 1H, J=8.3 Hz, 1.4 Hz), 7.02 (d, 1H, J=1.4 Hz), 3.66 (s,2H), 1.34 (s, 6H).

[1500] Step 7. Preparation of ethyl6-chloro-7-(2-acetoxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1501] The salicylaldehyde (Step 6) was chlorinated via a method similarto that described in Example 9 yielding5-chloro-4-(2-acetoxy-1,1-dimethylethyl)salicylaldehyde. Thissalicylaldehyde was converted to the substituted ethyl2H-1-benzopyran-3-carboxylate via a method similar to that described inExample 1, Step 1: ¹H NMR (CDCl₃/300 MHz) 7.63 (s, 1H), 7.22 (s, 1H),7.02 (s, 1H), 5.70 (q, 1H, J=6.8 Hz), 4.46 (s, 2H), 4.32 (m, 2H), 1.97(s, 3H), 1.49 (s, 6H), 1.36 (t, 3H, J=7.0 Hz). ¹⁹F NMR (CDCl₃/282 MHz)−78.8 (d, J=6.5 Hz).

[1502] Step 8. Preparation of6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1503] The ester obtained from Step 7 was hydrolyzed to the carboxylicacid via a method similar to that described in Example 1, Step 2: mp203.8-205.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.50 (s, 1H),7.21 (s, 1H), 5.83 (q, 1H, J=7.0 Hz), 3.90 (s, 2H), 1.46 (s, 6H). ¹⁹FNMR (acetone-d₆/282 MHz) −79.4 (d, J=7.2 Hz). ESHRMS m/z 349.0443 (M−H,Calc'd 349.0454). Anal. Calc'd for C₁₅H₁₄ClF₃O₄: C, 51.37; H, 4.02; Cl,10.11. Found: C, 51.24; H, 4.02; Cl, 10.45.

EXAMPLE 179

[1504]

[1505]7-(2-Hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1506] The salicylaldehyde from Example 178, Step 6 was converted to thetitle compound via a procedure similar to that described in Example 11,Steps 2 and 3: mp 228.9-230.0° C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s,1H), 7.37 (d, 1H, J=8.1 Hz), 7.17 (dd, 1H, J=8.1 Hz, 1.6 Hz), 7.08 (s,1H), 5.81 (q, 1H, J=7.2 Hz), 3.60 (s, 2H), 1.30 (s, 6H). ¹⁹F NMR(acetone-d₆/282 MHz) −79.5 (d, J=7.2 Hz). ESHRMS m/z 315.0843 (M−H,Calc'd 315.0844). Anal. Calc'd for C₁₇H₁₀ClF₃O₄: C, 56.96; H, 4.78.Found: C, 56.91; H, 4.85.

EXAMPLE 180

[1507]

[1508] 6-Chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1509] 3-Iodophenol was converted to the title compound by a proceduresimilar to that described in Example 100: mp 224.9-225.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.92 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 5.91 (q,1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.3 (d, J=7.2 Hz). FABLRMSm/z 403 (M−H). ESHRMS m/z 402.8836 (M−H, Calc'd 402.8846). Anal. Calc'dfor C₁₁H₅ClF₃IO₃: C, 32.66; H, 1.25; Cl, 8.76. Found: C, 32.65; H, 0.97:Cl, 8.39.

EXAMPLE 181

[1510]

[1511]6-Chloro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1512] The title compound was prepared from ethyl6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 180) via a procedure similar to that described in Example 118:mp >300° C. ¹H NMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.68 (s, 1H), 7.24(s, 1H), 5.90 (q, 1H, J=7.0 Hz), 4.23 (s, 1H). ¹⁹F NMR (acetone-d₆/282MHz) −79.3 (d, J=6.5 Hz). FABLRMS m/z 301 (M−H). ESHRMS m/z 300.9884(M−H, Calc'd 300.9879). Anal. Calc'd for C₁₃H₆ClF₃O₃: C, 51-59; H, 2.00;Cl, 11.71. Found: C, 51.63; H, 2.04; Cl, 11.84.

EXAMPLE 182

[1513]

[1514]6-Chloro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1515] The title compound was prepared from ethyl6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 180) via a procedure similar to that described in Example 114:mp >200° C. with decomposition. ¹H NMR (acetone-d₆/300 MHz) 7.89 (s,1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.07 (dd, 1H, J=17.5 Hz, 11.1 Hz), 6.07(d, 1H, J=17.3 Hz), 5.87 (q, 1H, J=7.0 Hz), 5.57 (d, 1H, J=11.1 Hz). ¹⁹FNMR (acetone-d₆/282 MHz) −79.2 (d, J=7.2 Hz). FABLRMS m/z 303 (M−H).ESHRMS m/z 303.0030 (M−H, Calc'd 303.0036). Anal. Calc'd forC₁₃H₈ClF₃O₃: C, 51.25; H, 2.65; Cl, 11.64. Found: C, 51.41; H, 2.66; Cl,11.68.

EXAMPLE 183

[1516]

[1517]6-Chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1518] Step 1. Preparation of 5-chloro-4-fluorosalicylaldehyde.

[1519] 4-Chloro-3-fluorophenol (Avocado product #16029) was converted tothe salicylaldehyde via a method similar to that described in Example 2,Step 1: mp 102.7-103.7° C. ¹H NMR (CDCl₃/300 MHz) 11.22 (d, 1H, J=1.6Hz), 9.80 (s, 1H), 7.63 (d, 1H, J=7.9 Hz), 6.77 (d, 1H, J=10.3 Hz). ¹⁹FNMR (CDCl₃/282 MHz) −100.3 (t).

[1520] Step 2. Preparation of ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1521] The salicylaldehyde (Step 1) was converted to the substitutedethyl 2H-1-benzopyran-oxylate via a method similar to that described inExample 11 (Steps 2,3), Step 2: mp 97.6-98.6° C. ¹H NMR (CDCl₃/300 MHz)7.63 (s, 1H), 7.29 (d, 1H, J=9.7 Hz), 6.84 (d, 1H, J=9.3 Hz), 5.69 (q,1H, J=6.6 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ¹⁹F NMR (CDCl₃/282MHz) −78.8 (d, J=6.5 Hz), −106.7 (t, J=8.7 Hz).

[1522] Step 3. Preparation of ethyl6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1523] A 50 mL flask was charged with the substituted ethyl2H-1-benzopyran-3-carboxylate from Step 2 (1.44 g, 4.43 mmol),4-methoxyphenol (0.62 g, 4.99 mmol), K₂CO₃ (0.84 g, 6.07 mmol), and DMSO(10 mL). The reaction was stirred at 105° C. for 18 hours, poured intowater extracted with ethyl acetate, washed with water, brine, dried overMgSO₄ and concentrated in vacuo, to give a brown oil which was passedthrough a column of silica gel with 5% ethyl acetate/hexanes to give ayellow solid (0.78 g, 41%): mp 115.8-117.0° C. ¹H NMR (CDCl₃/300 MHz)7.66 (s, 1H), 7.32 (s, 1H), 7.04 (d, 2H, J=9.3 Hz), 6.98 (d, 2H, J=9.1Hz), 6.38 (s, 1H), 5.65 (q, 1H, J=6.8 Hz), 4.33 (m, 2H), 3.86 (s, 3H),1.37 (t, 3H, J=7.2 Hz). ¹⁹F NMR (CDCl₃/282 MHz) −78.9 (d, J=6.5 Hz).

[1524] Step 4. Preparation of6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1525] The ester (Step 3) was hydrolyzed to the carboxylic acid via amethod similar to that described in Example 1, Step 2: mp 213.2-214.3°C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.70 (s, 1H), 7.13 (d, 2H,J=9.3 Hz), 7.09 (d, 2H, J=8.9 Hz), 6.42 (s, 1H), 5.83 (q, 1H, J=7.0 Hz),3.87 (s, 3H). ¹⁹F NMR (acetone-d₆/282 MHz) −79.5 (d, J=7.2 Hz). FABLRMSm/z 401 (M+H). ESHRMS m/z 418.0799 (M+NH₄, Calc'd 418.0669). Anal.Calc'd for C₁₈H₁₂ClF₃O₅: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 54.17;H, 3.03; Cl, 8.91.

EXAMPLE 184

[1526]

[1527]6-Chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2B-1-benzopyran-3-carboxylicacid

[1528] The title compound was prepared from 4-chlorophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 205.4-206.5° C. ¹H NMR (acetone-d₆/300MHz) 7.93 (s, 1H), 7.75 (s, 1H), 7.50 (d, 2H, J=8.9 Hz), 7.19 (d, 2H,J=8.9 Hz), 6.69 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). ¹⁹F NMR(acetone-d₆/282MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 403 (M-H). ESHRMSm/z 402.9773 (M−H, Calc'd 402.9752). Anal. Calc'd for C₁₇H₉Cl₂F₃O₄: C,50.40; H, 2.24; Cl, 17.50. Found: C, 50.02; H, 1.98; Cl, 17.79.

EXAMPLE 185

[1529]

[1530] 6-Chloro-7-(4-cyanophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

[1531] The title compound was prepared from 4-cyanophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 212.5-215.7° C. ¹H NMR (acetone-d₆/300MHz) 7.96 (s, 1H), 7.90 (d, 2H, J=8.9 Hz), 7.81 (s, 1H), 7.27 (d, 2H,J=8.9 Hz), 6.96 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). ¹⁹F NMR(acetone-d₆/282MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 396 (M+H). ESHRMSm/z 413.0544 (M+NH₄, Calc'd 413.0516). Anal. Calc'd for C₁₈H₉ClF₃NO₄: C,54.63; H, 2.29; N, 3.54; Cl, 8.96. Found: C, 54.40; H, 2.18; N 3.30; Cl,9.20.

EXAMPLE 186

[1532]

[1533]6-Chloro-2-(trifluoromethyl)-7-[4-(trifluoromethyl)phenoxy]-2H-1-beazopyran-3-carboxylicacid

[1534] The title compound was prepared from 4-(trifluoromethyl)phenoland ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 230.9-232.0° C. ¹H NMR (acetone-d₆/300MHz) 7.93 (s, 1H), 7.77 (m, 3H), 7.27 (d, 2H, J=8.7 Hz), 6.86 (s, 1H),5.87 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282MHz) −62.8 (s, 3F), −79.4(d, 3F, J=7.2 Hz). ESLRMS m/z 437 (M−H). ESHRMS m/z 437.0008 (M−H,Calc'd 437.0015). Anal. Calc'd for C₁₈H₉ClF₆O₄: C, 49.28; H, 2.07; Cl,8.08. Found: C, 49.25; H, 2.08; Cl, 8.24.

EXAMPLE 187

[1535]

[1536]6-Chloro-2-(trifluoromethyl)-7-[4-(trifluoromethoxy)phenoxy]-2H-1-benzopyran-3-carboxlicacid

[1537] The title compound was prepared from 4-(trifluoromethoxy)phenoland ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 198.0-199.2° C. ¹H NMR (acetone-d₆/300MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.43 (d, 2H, J=9.1 Hz), 7.25 (d, 2H,J=9.1 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282MHz) −59.4 (s, 3F), −79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 453 (M−H).ESHRMS m/z 452.9950 (M−H, Calc'd 452.9964). Anal. Calc'd forC₁₈H₉ClF₆O₅: C, 47.55; H, 2.00; Cl, 7.80. Found: C, 47.47; H, 1.89; Cl,8.02.

EXAMPLE 188

[1538]

[1539]7-(2-Bromo-4-chlorophenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1540] The title compound was prepared from 2-bromo-4-chlorophenol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 223.6-225.6° C. ¹H NMR (acetone-d₆/300MHz) 7.89 (s, 1H), 7.83 (d, 1H, J=2.6 Hz), 7.73 (s,1H), 7.52 (dd, 1H,J=8.7 Hz, 2.4 Hz), 7.25 (d, 1H, J=8.9 Hz), 6.55 (s, 1H), 5.83 (q, 1H,J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z481 (M−H). ESHRMS m/z,480.8856 (M−H, Calc'd 480.8857). Anal. Calc'd forC₁₇H₈BrCl₂F₃O₄: C, 42.18; H, 1.67; Br, 16.51; Cl, 14.65. Found: C,42.15; H, 1.54; Br, 16.56; Cl, 14.39.

EXAMPLE 189

[1541]

[1542]7-[(6-Bromo-2-naphthalenyl)oxy]-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1543] The title compound was prepared from 6-bromo-2-napthol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 252.6-254.8° C. ¹H NMR (acetone-d₆/300MHz) 8.19 (s, 1H), 8.04 (d, 1H, J=9.1 Hz), 7.93 (s, 1H), 7.87 (d, 1H,J=8.9 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.55 (s, 1H), 7.43 (d,1H, J=9.1 Hz), 6.72 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). ¹⁹F NMR(acetone-d₆/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMS m/z 497 (M−H). ESHRMSm/z 496.9421 (M−H, Calc'd 496.9403). Anal. Calc'd for C₂₁H₁₁BrClF₃O₄with 1.75 wt % H₂O: C, 49.60; H, 2.38; Br, 15.71; Cl, 6.97. Found: C,49.55; H, 2.03; Br, 15.56; Cl, 7.22.

EXAMPLE 190

[1544]

[1545]6-Chloro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1546] The title compound was prepared from 2,6-dimethylphenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 252.7-258.6° C. ¹H NMR (acetone-d₆/300MHz) 7.88 (s, 1H), 7.71 (s, 1H), 7.22 (m, 3H), 6.04 (s, 1H), 5.77 (q,1H, J=7.0 Hz), 2.13 (s, 6H). ¹⁹F NMR (acetone-d₆/282 MHz) −79.6 (d,J=7.2 Hz). FABLRMS m/z 397 (M−H). ESHRMS m/z 397.0450 (M−H, Calc'd397.0454). Anal. Calc'd for C₁₉H₁₄ClF₃O₄: C, 57.23; H, 3.54; Cl, 8.89.Found: C, 57.21; H, 3.56; Cl, 8.98.

EXAMPLE 191

[1547]

[1548]6-Chloro-7-[(4-methoxyphenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1549] The title compound was prepared from 4-methoxybenzenethiol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 239.4-242.3° C. ¹H NMR (acetone-d₆/300MHz) 7.84 (s, 1H), 7.55 (m, 3H), 7.16 (d, 2H, J=8.7 Hz), 6.20 (s, 1H),5.75 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4(d, J=6.5 Hz). ESLRMS m/z 415 (M−H). ESHRMS m/z 415.0005 (M−H, Calc'd415.0019). Anal. Calc'd for C₁₈H₁₂ClF₃O₄S: C, 51.87; H, 2.90; Cl, 8.51;S, 7.69. Found: C, 51.76; H, 2.83; Cl 8.55; S, 7.77.

EXAMPLE 192

[1550]

[1551]6-Chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1552] The title compound was prepared from 4-chlorobenzenethiol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 251.7-253.3° C. ¹H NMR (acetone-d₆/300MHz) 7.86 (s, 1H), 7.62 (m, SH), 6.39 (s, 1H), 5.78 (q, 1H, J=7.0 Hz).¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=6.5 Hz). ESLRMS m/z 419 (M−H).ESHRMS m/z 418.9559 (M−H, Calc'd 418.9523). Anal. Calc'd forC₁₇H₉Cl₂F₃O₃S: C, 48.47; H, 2.15; Cl, 16.83; S, 7.61. Found: C, 48.38;H, 2.12; Cl, 17.09; S, 7.75.

EXAMPLE 193

[1553]

[1554]6-Chloro-7-[(4-chlorophenyl)sulfinyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1555] Following a procedure similar to that described in Example 128,ethyl6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 192) was treated with OXONE® yielding the products labeledExample 193 and Example 194: mp 213.8-217.4° C. ¹H NMR (acetone-d₆/300MHz) 7.91 (s, 1H), 7.83 (d, 2H, J=8.7 Hz), 7.62 (m, 4H), 5.98 (q, 1H,J=6.8 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.3 (d, J=7.2 Hz). ESLRMS m/z435 (M−H). ESHRMS m/z 434.9470 (M−H, Calc'd 434.9472). Anal. Calc'd forC¹⁷H₉Cl₂F₃O₄S: C, 46.70; H. 2.07; Cl, 16.22; S, 7.33. Found: C, 46.80;H, 2.28; Cl, 16.75; S, 7.39.

EXAMPLE 194

[1556]

[1557]6-Chloro-7-[(4-chlorophenyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1558] mp 240.4-241.5° C. ¹H NMR (acetone-d₆/300 MHz) 8.04 (d, 2H, J=8.9Hz), 7.92 (s, 2H), 7.75 (s, 1H), 7.72 (d, 2H, J=8.7 Hz), 6.02 (q, 1H,J=6.8 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.2 (d, J=7.4 Hz). ESLRMS m/z451 (M−H). ESHRMS m/z 450.9409 (M−H, Calc'd 450.9422). Anal. Calc'd forC₁₇H₉Cl₂F₃O₅S: C, 45.05; H, 2.00; Cl, 15.64. Found: C, 45.35; H, 2.05;Cl, 16.01.

EXAMPLE 195

[1559]

[1560]6-Chloro-7-(phenylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1561] The title compound was prepared from benzenethiol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 271.7-274.4° C. ¹H NMR (acetone-d₆/300MHz) 7.86 (s, 1H), 7.60 (m, 6H), 6.29 (s, 1H), 5.74 (q, 1H, J=7.0 Hz).¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 385 (M−H).ESHRMS m/z 384.9904 (M−H, Calc'd 384.9913). Anal. Calc'd forC₁₇H₁₀ClF₃O₃S: C, 52.79; H, 2.61; Cl, 9.17; S, 8.29. Found: C, 52.80; H,2.49; Cl, 9.71; S, 8.37.

EXAMPLE 196

[1562]

[1563]6-Chloro-7-(3-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1564] The title compound was prepared from 3-chlorophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 174.1-176.1° C. ¹H NMR (acetone-d₆/300MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.29 (d, 1H, J=7.5 Hz),7.17 (d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=8.3 Hz), 6.73 (s, 1H), 5.85 (q,1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMSm/z 403 (M−H). ESHRMS m/z 402.9752 (M−H, Calc'd 402.9729). Anal. Calc'dfor C₁₇H₉Cl₂F₃O₄: C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.18; H,2.00; Cl, 17.26.

EXAMPLE 197

[1565]

[1566]6-Chloro-7-(2,4-dichlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1567] The title compound was prepared from 2,4-dichlorophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 233.0-234.0° C. ¹H NMR (acetone-d₆/300MHz) 7.90 (s, 1H), 7.73 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.47 (dd, 1H,J=8.7 Hz, 2.6 Hz), 7.28 (d, 1H, J=8.7 Hz), 6.57 (s, 1H), 5.81 (q, 1H,J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMS m/z437 (M−H). ESHRMS m/z 436.9379 (M−H, Calc'd 436.9362). Anal. Calc'd forC₁₇H₉Cl₃F₃O₄: C, 46.45; H, 1.83; Cl, 24.19. Found: C, 46.38; H, 1.59;Cl, 24.46.

EXAMPLE 198

[1568]

[1569]6-Chloro-7-(3,4-difluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1570] The title compound was prepared from 3,4-difluorobenzenethiol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 191.9-193.1° C. ¹H NMR (acetone-d₆/300MHz) 7.90 (s, 1H), 7.72 (d, 1H, J=3.0 Hz), 7.45 (q, 1H, J=9.1 Hz), 7.21(m, 1H), 7.00 (m, 1H), 6.70 (d, 1H, J=2.6 Hz), 5.84 (q, 1H, J=7.0 Hz).¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, 3F, J=6.5 Hz), −136.4 (m, 1F),−145.1 (m, 1F). FABLRMS m/z 405 (M−H). ESHRMS m/z 404.9923 (M−H, Calc'd404.9953). Anal. Calc'd for C₁₇H₈ClF₅O₄: C, 50.21; H, 1.98; Cl, 8.72.Found: C, 50.14; H, 1.73; Cl, 8.93.

EXAMPLE 199

[1571]

[1572]6-Chloro-7-[(6-chloro-2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1573] The title compound was prepared from 6-chloro-2-pyridinol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 226.4-227.4° C. ¹H NMR (acetone-d₆/300MHz) 7.99 (m, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.30 (d, 1H, J=7.7 Hz),7.16 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). ¹⁹F NMR(acetone-d₆/282 MHz)-79.3 (d, J=7.2 Hz). FABLRMS m/z 404 (M−H). ESHRMSm/z 405.9853 (M+H, Calc'd 405.9861). Anal. Calc'd for C₁₆H₈Cl₂F₃NO₄: C,47.32; H, 1.99; N, 3.45; Cl, 17.46. Found: C, 47.26; H, 1.93; N, 3.35;Cl, 17.19.

EXAMPLE 200

[1574]

[1575]6-Chloro-7-[(2-chloro-3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1576] The title compound was prepared from 2-chloro-3-pyridinol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 213.4-216.2° C. ¹H NMR (acetone-d₆/300MHz) 8.33 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.64 (m, 1H), 7.53 (m,1H), 6.67 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz)−79.4 (d, J=7.2 Hz). ESHRMS m/z 405.9890 (M+H, Calc'd 405.9861). Anal.Calc'd for C₁₆H₈Cl₂F₃NO₄: C, 47.32; H, 1.99; N, 3.45; Cl, 17.46. Found:C, 47.36; H, 1.98; N, 3.40; Cl, 17.14.

EXAMPLE 201

[1577]

[1578]6-Chloro-7-[3-pyridinyloxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1579] The title compound was prepared from 3-hydroxypyridine and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 237.8-238.8° C. ¹H NMR (DMSO-d₆/300 MHz)13.3 (br s, 1H), 8.42 (m, 2H), 7.87 (s, 1H), 7.83 (s, 1H), 7.48 (m, 2H),6.72 (s, 1H), 5.93 (q, 1H, J=7.2 Hz). ¹⁹F NMR (DMSO-d₆/282 MHz) −77.8(d, J=7.2 Hz). FABLRMS m/z 372 (M+H). ESHRMS m/z 370.0083 (M−H, Calc'd370.0094). Anal. Calc'd for C₁₆H₉ClF₃NO₄: C, 51.70; H, 2.44; N, 3.77;Cl, 9.54. Found: C, 51.49; H, 2.47; N, 3.70; Cl, 9.69.

EXAMPLE 202

[1580]

[1581]6-Chloro-7-[2-pyridinyloxy]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1582] The title compound was prepared from 2-hydroxypyridine and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 234.2-235.4° C. ¹H NMR (acetone-d₆/300MHz) 8.14 (dd, 1H, J=4.8 Hz, 1.4 Hz), 7.92 (m, 2H), 7.70 (s, 1H), 7.14(m, 2H), 6.99 (s, 1H), 5.88 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282MHz) −79.4 (d, J=7.2 Hz). ESLRMS m/z 372 (M+H). ESHRMS m/z 372.0252(M+H, Calc'd 372.0250). Anal. Calc'd for C₁₆H₉ClF₃NO₄: C, 51.70; H,2.44; N, 3.77; Cl, 9.54. Found: C, 51.70; H, 2.44; N, 3.71; Cl, 9.65.

EXAMPLE 203

[1583]

[1584]6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1585] The title compound was prepared from 4-nitrophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 246.4-248.3° C. ¹H NMR (acetone-d₆/300MHz) 8.34 (d, 2H, J=9.3 Hz), 7.96 (s, 1H), 7.82 (s, 1H), 7.29 (d, 2H,J=9.3 Hz), 7.02 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₅/282MHz) −79.3 (d, J=7.2 Hz). ESLRMS m/z 433 (M+NH₄). ESHRMS m/z 433.0463(M+NH₄, Calc'd 433.0414). Anal. Calc'd for C₁₇H₉ClF₃NO₆: C, 49.12; H,2.18; N, 3.37; Cl, 8.53. Found: C, 48.94; H, 2.05; N, 3.32; Cl, 8.72.

EXAMPLE 204

[1586]

[1587]6-Chloro-7-(2-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1588] The title compound was prepared from 2-chlorophenol and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 199.0-199.1° C. ¹H NMR (acetone-d₆/300MHz) 7.94 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 7.51 (m, 1H), 7.38 (m,1H), 7.32 (m, 1H), 6.44 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). ¹⁹F NMR(acetone-d₆/282 MHz) −79.5 (d, J=6.5 Hz). ESHRMS m/z 402.9752 (M−H,Calc'd 402.9751). Anal. Calc'd for C₁₇H₉Cl₂F₃O₄: C, 50.40; H, 2.24; Cl,17.50. Found: C, 50.42; H, 2.12; Cl, 17.72.

EXAMPLE 205

[1589]

[1590] 6-Chloro-7-(4-chlro-3-fluorophenoxy)-2-(trifluoromethyl)-2H-1-benzapyran-3-carboxylicacid

[1591] The title compound was prepared from 4-chloro-3-fluorophenol andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4: mp 206.8-207.4° C. ¹H NMR (acetone-d₆/300MHz) 7.92 (s, 1H), 7.74 (s, 1H), 7.59 (m, 1H), 7.16 (m, 1H), 6.99 (m,1H), 6.83 (s, 1H), 5.86 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz)−79.4 (d, 3F, J=6.5 Hz), −113.8 (m, 1F). Anal. Calc'd for C₁₇H₈Cl₂F₄O₄:C, 48.25; H, 1.91; Cl, 16.76. Found: C, 48.20; H, 1.97; Cl, 16.92.

EXAMPLE 206

[1592]

[1593]7-(4-Carboxyphenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1594] The title compound was prepared from 4-hydroxybenzoic acid andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4. (Note: In the step similar to step 3, anadditional equivalent of potassium carbonate was added.) mp >300° C. ¹HNMR (acetone-d₆/300 MHz) 8.16 (d, 2H, J=8.9 Hz), 7.96 (s, 1H), 7.79 (s,1H), 7.20 (d, 2H, J=8.9 Hz), 6.87 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). ¹⁹FNMR (acetone-d₆/282 MHz) −79.4 (d, J=7.2 Hz). ESHRMS m/z 413.0006 (M−H,Calc'd 413.0040). Anal. Calc'd for C₁₈H₁₀ClF₃O₆: C, 52.13; H, 2.43.Found: C, 51.81; H, 2.31.

EXAMPLE 207

[1595]

[1596]7-(4-Carboxy-2-chloro-phenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1597] The title compound was prepared from 3-chloro-4-hydroxybenzoicacid and ethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4. (Note: In the step similar to Example 183,Step 3, an additional equivalent of potassium carbonate was added.)mp >300° C. ¹H NMR (acetone-d₆/ 300 MHz) 8.18 (d, 1H, J=2.0 Hz), 8.03(dd, 1H, J=8.5 Hz 2.0 Hz), 7.93 (s, 1H), 7.78 (s, 1H), 7.23 (d, 1H,J=8.7 Hz), 6.77 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282MHz) −79.4 (d, J=6.5 Hz). ESHRMS m/z 446.9625 (M−H, Calc'd 446.9650).Anal. Calc'd for C₁₈H₉Cl₂F₃O₆: C, 48.13; H, 2.02; Cl, 15.79. Found: C,47.96; H, 1.90; Cl, 15.65.

EXAMPLE 208

[1598]

[1599]7-(3-Carboxyphenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1600] The title compound was prepared from 3-hydroxybenzoic acid andethyl6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 183, Step 2) via a procedure similar to that described inExample 183, Steps 3 and 4. (Note: In the step similar to step 3, anadditional equivalent of potassium carbonate was added.) mp 288.1-289.2°C. ¹H NMR (acetone-d₆/300 MHz) 7.92 (m, 2H), 7.75 (s, 1H), 7.68 (d, 1H,J=1.4 Hz) , 7.62 (t, 1H, J=7.9 Hz) , 7.41 (m, 1H), 6.72 (s, 1H), 5.85(q, 1H, J=7.0 Hz). ¹⁹F NMR (acetone-d₆/282 MHz) −79.4 (d, J=6.5 Hz)ESHRMS m/z 413.0027 (M−H, Calc'd 413.0040). Anal. Calc'd forC₁₈H₁₀ClF₃O₆: C, 52.13; H, 2.43; Cl, 8.55. Found: C, 51.88; H, 2.48; Cl,8.65.

EXAMPLE 209

[1601]

[1602]6-Chloro-7-(2,2,2-trifluoromethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

[1603] Step 1. Preparation of ethyl6-Chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

[1604] A solution of 2,2,2-trifluoroethanol(1.3 g, 13 mmol) in1,4-dioxane (2 mL) was added to a slurry of NaH (0.5 g, 13 mmol) in1,4-dioxane (2 mL). The reaction was stirred for 10 minutes then asolution of6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(1.61 g, 5.0 mmol) in 1,4-dioxane (5 mL) was added and the reaction washeated to 85° C. for 22 hours. The reaction mixture was acidified with3N HCl, extracted with ethyl acetate, washed with saturated NaHCO₃,brine, dried over MgSO₄ and concentrated in vacuo, to give a brown oilwhich was passed through a column of silica gel with 10% ethylacetate/hexanes to give a white solid (0.37 g, 18%): ¹H NMR (CDCl₃/300MHz) 7.62 (s, 1H), 7.28 (s, 1H), 6.58 (s, 1H), 5.69 (q, 1H, J=6.6 Hz),4.42 (m, 2H), 4.31 (m, 2H), 1.34 (t, 3H, J=7.1 Hz). ¹⁹F NMR (CDCl₃/282MHz) −74.2 (t, 3F, J=8.0 Hz), −78.9 (d, 3F, J=6.5 Hz).

[1605] Step 2. Preparation of6-Chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

[1606] The ester (Step 1) was hydrolyzed to the carhoxylic acid via amethod similar to that described in Example 1, Step 2: mp 174.4-176.0°C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.62 (s, 1H), 7.00 (s, 1H),5.86 (q, 1H, J=7.0 Hz), 4.90 (m, 2H). ¹⁹F NMR (acetone-d₆/282 MHz) −75.1(t, 3F, J=8.7 Hz), −79.5 (d, 3F, J=7.2 Hz). FABLRMS m/z 375 (M−H).ESHRMS m/z 374.9880 (M−H, Calc'd 374.9859).

EXAMPLE 210

[1607]

[1608] 1,2-Dihydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1609] Step 1. Preparation of ethyl6-trimethylsilylethynyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

[1610] The ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example160, Step 1) (750 mg, 1.89 mmol), trimethylsilylacetylene (925 mg, 9.44mmol), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol),copper(I)iodide (9.5 mg, 0.05 mmol), and triethylamine (953 mg, 9.44mmol) were mixed at room temperature for 2 h in acetonitrile (10 mL).The resulting black heterogeneous mixture was poured into ethylacetate(50 mL) and extracted with water (2×25 mL), 1 N aqueoushydrochloric acid (25 mL), and saturated aqueous ammonium chloride (2×25mL). The organic layer was dried over sodium sulfate and solvent removedat reduce pressure. The product was purified by flash chromatography(0-25% ethyl acetate/hexanes, silica gel). A black semisolid wasisolated which upon trituration with hexanes afforded ethyl6-trimethylsilylethynyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylateas a yellow solid(267 mg,38%): mp 117-119° C. ¹H NMR (CDCl₃, 300 MHz)7.65 (s, 1H), 7.24-7.32 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.08-5.18 (m,1H), 4.66 (brs, 1H), 4.24-4.64 (m, 2H), 1.34 (t, 3H, J=7.1 Hz) 0.22 (s,9H). ESHRMS m/z 368.1306 (Calc'd for M+H 368.1293).

[1611] Step 2: Preparation of1,2-dihydro-6-ethynyl-2-(trifluoromethyl)-3-quinolinecarboxylic acid.

[1612] Hydrolysis of the ester and the trimethylsilyl moiety of ethyl6-trimethylsilylethynyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate(Step 1) was performed by a procedure similar to that described inExample 157, Step 3, yielding the title compound: mp 259-268° C. ¹H NMR(CD₃OD, 300 MHz) 7.69 (s, 1H), 7.21-7.28 (m, 2H), 6.65 (d, 1H, J=8.4Hz), 5.11 (q, 1H, J=7.3 Hz). ESHRMS m/z 268.0580 (Calc'd for M+H268.0586).

EXAMPLE 211

[1613]

[1614]1,2-Dihydro-6-(phenylethynyl)-2-(trifluoromethyl)-3-quinolinecarboxylicacid

[1615] Ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example160, Step 1) was converted to the title compound by a procedure similarto that described in Example 210: mp 218-219° C. ¹H NMR (CDCl₃/DMSO-d₆(19:1), 400 MHz) 7.56 (s, 1H), 7.35 (d, 1H, J=8.5 Hz), 7.18-7.24 (m,6H), 6.57 (d, 1H, J=8.5 Hz), 5.93 (bs, 1H), 5.03-5.05 (m, 1H). FABHRMSm/z 344.0898 (Calc'd for M+H 344.0901).

EXAMPLE 212

[1616]

[1617] 6-Chloro-4-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

[1618] Step 1. Preparation ofethyl-6-chloro-4-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

[1619]Ethyl-6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate(Example 142,Step 5)(0.433 g, 1.30 mmol) was dissolved in methanol (10mL). Palladium(5 wt % on activated carbon)(0.150 g) was slowly added.The reaction vessel was charged with hydrogen (25 psi) and was stirredfor 25 minutes. Gas chromatographic analysis indicated that the reactionwas complete. The reaction mixture was filtered through Celite andevaporated to yield a orange oil. The oil was purified by flash columnchromatography(100 % hexanes) to yield the desired product as a yellowoil (0.282 g, 65%): ¹H NMR (CDCl₃/300 MHz) 7.43 (d, 1H, J=2.4 Hz), 7.25(dd, 1H, J=2.4, 8.7 Hz), 6.92(d, 1H, J=8.7 Hz), 5.75 (q, 1H, J=7.0 Hz),4.38−4.24 (m, 2H), 3.05−2.95 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.25, (t,3H, J=7.6 Hz).

[1620] Step 2. Preparation of6-chloro-4-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

[1621] The ester from Step 1 (0.282 g, 0.842 mmol) was dissolved in aTHF-EtOH-H₂O mixture (10 mL, 7:2:1). The resulting solution was treatedwith aqueous sodium hydroxide (0.340 mL, 0.842 mmol of a 2.5 N solution)and was stirred at room temperature for 18 hours. The solvent wasremoved in vacuo and the residue was dissolved in water 10 mL). Diethylether (10 ml ) was added and the resulting mixture acidified by theaddition of a few drops of concentrated HCl. The diethyl ether layer wasseparated, and the aqueous phase was extracted with additionalether(2×10 mL). The ether extracts were combined, dried over MgSO₄,filtered, and evaporated to yield a clear oil. Addition of hexane (10mL) resulted in the formation of a white precipitate which was collectedby vacuum filtration to afford the title compound (0.064 g, 25%) as awhite powder: mp 170.9-172.1° C. ¹H NMR (CDCl₃/300 MHz) 7.47 (d, 1H,J=2.4 Hz), 7.30 (dd, 1H, J=2.4, 8.7 Hz), 6.96 (d, 1H, J=8.7 Hz), 5.76(q, 1H, J=7.0 Hz), 3.08 (q, 2H, J=7.6 Hz), 1.27 (t, 3H, J=7.5 Hz).FABLRMS m/z 305.2 (M−H).ESHRMS m/z 305.0185 (M−H, Calc'd. 305.0192).Anal. Calc'd for C₁₃H₈ClF₃O₃: C, 50.92; H, 3.29; Cl, 11.56. Found: C,50.68; H, 3.18; Cl, 11.64.

[1622] Biological Evaluation

[1623] Rat Carrageenan Foot Pad Edema Test

[1624] The carrageenan foot edema test was performed with materials,reagents and procedures essentially as described by Winter, et al.,(Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley ratswere selected in each group so that the average body weight was as closeas possible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table I. TABLE I RAT PAW EDEMA ANALGESIA % Inhibition% Inhibition Example 30 mg/g body weight 30 mg/g body weight 1 57 58 843 36 12 30 37 16 48 34 24 29 25 31  39*  37* 32  59*  73* 38 47 55 3918 8 46 59 67 65 43 32 79 45 53 81 36 44 83 56 65 84 44 24 105 75 69 11552 62 139 42 41 156 54 66 157  44*  36* 158  45*  55* 161 53 56 165  30* 33* 172 57 67 177  59*  61* 188 57 69

[1625] Evaluation of COX-1 and COX-2 Activity In Vitro

[1626] The compounds of this invention exhibited inhibition in vitro ofCOX-2. The COX-2 inhibition activity of the compounds of this inventionillustrated in the Examples was determined by the following methods.

[1627] a. Preparation of Recombinant COX Baculoviruses

[1628] Recombinant COX-1 and COX-2 were prepared as described by Gierseet al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containingthe coding region of either human or murine COX-1 or human or murineCOX-2 was cloned into a BamH1 site of the baculovirus transfer vectorpVL1393 (Invitrogen) to generate the baculovirus transfer vectors forCOX-1 and COX-2 in a manner similar to the method of D. R. O'Reilly etal (Baculovirus Expression Vectors: A Laboratory Manual (1992)).Recombinant baculoviruses were isolated by transfecting 4 μg ofbaculovirus transfer vector DNA into SF9 insect cells (2×10⁸) along with200 ng of linearized baculovirus plasmid DNA by the calcium phosphatemethod. See M. D. Summers and G. E. Smith, A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures, Texas Agric.Exp. Station Bull. 1555 (1987). Recombinant viruses were purified bythree rounds of plaque purification and high titer (10⁷-10⁸ pfu/mL)stocks of virus were prepared. For large scale production, SF9 insectcells were infected in 10 liter fermentors (0.5×10⁶/mL) with therecombinant baculovirus stock such that the multiplicity of infectionwas 0.1. After 72 hours the cells were centrifuged and the cell pellethomogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1%3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Thehomogenate was centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at −80° C. before being assayed for COX activity.

[1629] b. Assay for COX-1 and COX-2 Activity

[1630] COX activity was assayed as PGE₂ formed/μg protein/time using anELISA to detect the prostaglandin released. CHAPS-solubilized insectcell membranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μM).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table II.

[1631] c. Fast Assay for COX-1 and COX-2 Activity

[1632] COX activity was assayed as PGE₂ formed/μg protein/time using anELISA to detect the prostaglandin released. CHAPS-solubilized insectcell membranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μMphenol,1 μM heme, 300 μM epinephrine) with the addition of 20 μl of 100μM arachidonic acid (10 μM). Compounds were pre-incubated with theenzyme for 10 minutes at 25° C. prior to the addition of arachidonicacid. Any reaction between the arachidonic acid and the enzyme wasstopped after two minutes at 37° C./room temperature by transferring 40μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. ThePGE₂ formed was measured by standard ELISA technology (Cayman Chemical).Results are shown in Table II. TABLE II COX-2 * COX-1 * COX-2 COX-1Example IC₅₀ μM IC₅₀ 82 M IC₅₀ μM IC₅₀ μM 1 0.3 45 2 <0.1 78 <0.1 5.0 6<0.1 >100 7 0.1 16 <0.1 1.0 8 <0.1 61 <0.1 21 9 <0.1 1.4 <0.1 <0.1 12 755 13 .3 >100 14 >100 >100 15 >0.1 11 133.6 44 16 <0.1 24 1.4 51 1812 >100 21 11 3.5 22 >100 >100 23 7 >100 24 >100 25 >100 78 26 >100 2027 67 >100 29 <0.1 >100 30 <0.1 1.2 16 3.8 31 <0.1 94 32 0.3 31 0.3 0.733 <0.1 5.7 8.2 28 35 2.2 8.9 1.7 11 38 0.2 6.2 25.7 57 39 0.2 451.3 >100 40 <0.1 24 74 43 42 <0.1 2.3 <0.1 11 43 99 85 44 0.3 72 21 >10045 0.2 47 46 >100 46 0.2 24 74 43 47 1.9 31 1.7 >100 49 24 >100 31 >10050 79 >100 52 20 >100 53 8 13 6 >100 54 19 >100 55 46 >100 53 >100 5612 >100 29 >100 57 21 10 21 >100 59 43 >100 63 1.4 >100 65 <0.1 1.0 6682 38 <0.1 16.9 67 <0.1 30 <0.1 6.7 81 <0.1 10.5 <0.1 1.6 82 <0.1 16<0.1 5.6 83 <0.1 9.6 <0.1 1.4 84 0.1 25 <0.1 2.8 88 <0.1 12.4 <0.1 6.491 <0.1 23 0.2 36 96 0.2 >100 0.3 100 97 0.2 78 0.1 25 98 2.0 >100 1.519 99 0.2 36 <0.1 23 101 <0.1 18 <0.1 16 103 36 61 104 <0.1 24 <0.1 8.2105 0.3 4.5 0.2 0.1 106 0.2 21 <0.1 5.7 114 <0.1 <0.1 <0.1 <0.1 115 <0.1<0.1 <0.1 <0.1 116 <0.1 <0.1 <0.1 <0.1 120 <0.1 98 <0.1 33 125 <0.1 0.2<0.1 <0.1 129 0.2 2.6 <0.1 0.3 138 0.3 42.5 <0.1 11.1 152 <0.1 74 <0.110 154 0.5 68.5 <0.1 37 155 <0.1 1.6 <0.1 <0.1 156 <0.1 0.8 <0.1 0.1 176<0.1 <0.1 2.0 3.3 177 <0.1 <0.1 <0.1 0.3 178 8.4 >100 14.7 >100 17915.6 >100 16.0 >100 180 <0.1 43.4 <0.1 >100 181 1.5 >100 >100 >100 182<0.1 >100 >100 >100 183 <0.1 0.1 <0.1 4.1 184 <0.1 <0.1 <0.1 1.3 185<0.1 68.4 <0.1 >100 186 <0.1 10.6 3.4 32.8 187 2.9 48.9 33.7 >100 188<0.1 1.3 <0.1 3.7 189 <0.1 56.2 1.2 44.8 190 0.5 0.5 0.5 37.4 191 <0.139.7 42.2 >100 192 <0.1 5.9 1.4 12.3 193 1.2 >100 >100 >100 195 <0.1 0.6<0.1 2.6 196 <0.1 10.1 9.5 30.3 197 <0.1 0.2 <0.1 0.4 198 <0.1 3.8 <0.112.4 199 <0.1 >100 200 <0.1 1.6 <0.1 28.5 201 <0.1 9.4 0.1 63.8 202 <0.142.8 203 <0.1 78.1 209 0.2 >100 >100 >100 210 1.7 88.8 10.0 >100 211 1.91.7 2.4 3.8

[1633] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Theactive compounds and composition may, for example, be administeredorally, pulmonary, mucosally, intravascularly, intraperitoneally,subcutaneously, intramuscularly or topically.

[1634] The phrase “co-therapy” (or “combination-therapy”), in defininguse of a cyclooxygenase-2 inhibitor agent and another pharmaceuticalagent, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as w 11 to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule having a fixed ratio of these activeagents or in multiple, separate capsules for each agent.

[1635] The phrase “therapeutically-effective” is intended to qualify theamount of each agent which will achieve the goal of improvement indisease severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

[1636] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

[1637] The amount of therapeutically active compounds which areadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely. The pharmaceutical compositions may contain active ingredientsin the range of about 0.1 to 2000 mg, preferably in the range of about0.5 to 500 mg and most preferably between about 1 and 100 mg. A dailydose of about 0.01 to 100 mg/kg body weight, preferably between about0.5 and about 20 mg/kg body weight and most preferably between about 0.1to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day.

[1638] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[1639] For inflammations of the eye or other external tissues, eg.,mouth and skin; the formulations are preferably applied as a topicalointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[1640] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier With aft or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

[1641] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[1642] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The antiinflammatory active ingredients arepreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

[1643] For therapeutic purposes, the active compounds of thiscombination invention are ordinarily combined with one or more adjuvantsappropriate to the indicated route of administration. If administeredper os, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[1644] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[1645] All mentioned references are incorporated by rerence as if herewritten. The priority applications (Ser. No. 60/044,485, filed Apr. 21,1997 and Ser. No. 09/062,537, filed Apr. 17, 1998) are also incorporatedby reference.

[1646] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A compound of Formula I″

wherein X is selected from O, S, CR^(c)R^(b) and NR^(a); wherein R^(a)is selected from hydrido, C₁-C₃-alkyl, (optionally substitutedphenyl)-C₁-C₃-alkyl, acyl and carboxy-C₁-C₆-alkyl; wherein each of R^(b)and R^(c) is independently selected from hydrido, C₁-C₃-alkyl,phenyl-C₁-C₃-alkyl, C₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio,C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c)forms a 3-6 membered cycloalkyl ring; wherein R is selected fromcarboxyl, aminocarbonyl, C₁-C₆-alkylsulfonylaminocarbonyl andC₁-C₆-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl, C₁-C₆-alkyl and C₂-C₆-alkenyl; wherein R¹ is selected fromC₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halo-C₁-C₆-alkynyl, aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl,aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy, methylenedioxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkyloxy,heteroaryl-C₁-C₆-alkyloxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ arecarbon; or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein X is selected from O, S, CR^(c)R^(b)and NR^(a); wherein R^(a) is selected from hydrido, C₁-C₃-alkyl,(optionally substituted phenyl)-C₁-C₃-alkyl, acyl andcarboxy-C₁-C₆-alkyl; wherein each of R^(b) and R^(c) is independentlyselected from hydrido, C₁-C₃-alkyl, phenyl-C₁-C₃-alkyl,C₁-C₃-perfluoroalkyl, chloro, C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro,cyano and cyano-C₁-C₃-alkyl; or wherein CR^(b)R^(c) forms a cyclopropylring; wherein R is selected from carboxyl, aminocarbonyl,C₁-C₆-alkylsulfonylaminocarbonyl and C₁-C₆-alkoxycarbonyl; wherein R″ isselected from hydrido, phenyl, thienyl, C₁-C₄-alkyl and C₂-C₄-alkenyl;wherein R¹ is selected from C₁-C₃-perfluoroalkyl, chloro,C₁-C₆-alkylthio, C₁-C₆-alkoxy, nitro, cyano and cyano-C₁-C₃-alkyl;wherein R²is one or more radicals independently selected from hydrido,halo, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl,aryl-C₁-C₃-alkyl, aryl-C₂-C₆-alkynyl, aryl-C₂-C₆-alkenyl, C₁-C₆-alkoxy,methylenedioxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, aryloxy, arylthio,arylsulfinyl, heteroaryloxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,aryl-C₁-C₆-alkyloxy, heteroaryl-C₁-C₆-alkyloxy,aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,C₁-C₃-(haloalkyl-C₁-C₃-hydroxyalkyl, C₁-C₆-hydroxyalkyl,hydroxyimino-C₁-C₆-alkyl, C₁-C₆-alkylamino, arylamino,aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-C₁-C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁-C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁-C₆-alkylaminosulfonyl, heteroaryl-C₁-C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁-C₆-alkylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁-C₆-alkoxycarbonyl,formyl, C₁-C₆-haloalkylcarbonyl and C₁-C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.
 3. A compound of claim 2 wherein X is selected from O, S andNR^(a); wherein R^(a) is selected from hydrido, C₁-C₃-alkyl and(optionally substituted phenyl)methyl; wherein R is carboxyl; wherein R″is selected from hydrido, C₁-C₃-alkyl and C₂-C₃-alkenyl; wherein R¹ isselected from C₁-C₃-perfluoroalkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halo-C₂-C₆-alkynyl, optionally substitutedphenyl-C₁-C₆-alkyl, optionally substituted phenyl-C₂-C₆-alkynyl,phenyl-C₂-C₆-alkenyl, C₁-C₃-alkoxy, methylenedioxy,C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio, C₁-C₃-alkylsulfinyl,optionally substituted phenyloxy, optionally substituted phenylthio,optionally substituted phenylsulfinyl,C₁-C₃-haloalkyl-C₁-C₃-hydroxyalkyl, phenyl-C₁-C₃-alkyloxy-C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, C₁-C₃-haloalkylthio,C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, hydroxyimino-C₁-C₃-alkyl,C₂-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁-C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁-C₆-alkyl)aminosulfonyl, phenyl-C₁-C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁-C₆-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁-C₆-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁-C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.
 4. A compound of claim 3wherein X is selected from O, S and NR^(a); wherein R^(a) is selectedfrom hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl,(4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected fromhydrido, ethyl and ethenyl; wherein R¹ is selected from trifluoromethyland pentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.
 5. A compound of claim 4selected from compounds, and their isomers andpharmaceutically-acceptable salts, of the group consisting of7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic;6-chloro-7-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(4-cyanophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-2-(trifluoromethyl)-7-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid;6-chloro-2-(trifluoromethyl)-7-[4-(trifluoromethoxy)phenoxy]-2H-1-benzopyran-3-carboxylicacid;7-(2-bromo-4-chlorophenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;7-[(6-bromo-2-naphthalenyl)oxy]-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(2,6-dimethylphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-[(4-methoxyphenyl)thiol-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-[(4-chlorophenyl)thiol-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-[(4-chlorophenyl)sulfinyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-[(4-chlorophenyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid;6-chloro-7-(phenylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid; 6-chloro-7-(3-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid; 6-chloro-7-(2,4-dichlorophenoxy)-2-(trifluoromethyl) -2H-1-benzopyran-3- carboxylicacid; 6-chloro-7-(3,4-difluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-[(6-chloro-2-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid;6-chloro-7-[(2-chloro-3-pyridinyl)oxy]-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid;6-chloro-7-[3-pyridinyloxy]-2-(trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-7-[2-pyridinyloxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-(2-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-(4-chloro-3-fluorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;7-(4-carboxyphenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;7-(4-carboxy-2-chlorophenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;7-(3-carboxyphenoxy)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;6-chloro-7-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;1,2-dihydro-6-ethynyl-2-((trifluoromethyl))-3-quinolinecarboxylic acid;and 1,2-dihydro-6-phenylethynyl-2-(trifluoromethyl)-3-quinolinecarboxylic acid.
 6. A compound of Formula IIa

wherein R³ is selected from hydrido, C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl,C₁-C₃-alkoxy and halo; wherein R⁴ is selected from hydrido, halo,C₁-C₄-alkyl, C₁-C₃-alkylthio, C₁-C₃-haloalkyl, amino, aminosulfonyl,C₁-C₃-alkylsulfonyl, C₁-C₃-alkylsulfinyl, C₁-C₃-alkoxy-C₁-C₃-alkyl,C₁-C₃-alkylcarbonyl, formyl, cyano, C₀-C₃-haloalkylthio, substituted orunsubstituted phenylcarbonyl, C₁-C₁-haloalkoxy, C₁-C₃-alkoxy,aryl-C₁-C₃-alkylcarbonyl, di-C₁-C₃-alkylaminosulfonyl,C₁-C₃-alkylaminosulfonyl, aryl-C₁-C₃-alkylaminosulfonyl, 5- or6-heteroaryl-C₁-C₃-alkylaminosulfonyl, 5- or 6-membered heteroaryl,C₁-C₃-hydroxyalkyl, substituted or unsubstituted phenyl and 5- or6-membered nitrogen-containing heterocyclylsulfonyl; wherein R⁵ isselected from hydrido, C₁-C₃-alkyl, halo, C₁-C₃-haloalkyl, C₁-C₄-hydroxyalkyl, C₂-C₃-alkynyl, C₂-C₃-alkenyl, C₁-C₃- alkoxy, phenoxy,phenoxy independently substituted with one or more radicals selectedfrom C₁-C₃-haloalkyl, nitro, carboxy, C₁-C₃- haloalkoxy, C₁-C₃-alkoxy,cyano, C₁-C₃-alkyl and halo, naphthyloxy, naphthyloxy substituted withone or more halo radicals, phenylthio, phenylthio substituted with oneor more halo radicals, phenylsulfinyl, phenylsulfinyl substituted withone or more halo radicals, phenylsulfonyl, phenylsulfonyl substitutedwith one or more halo radicals, pyridinyloxy, pyridinyloxy substitutedwith one or more halo radicals, and phenyl; and wherein R⁶is selectedfrom hydrido, halo, cyano, hydroxyiminomethyl, C₁-C₃-hydroxyalkyl,C₂-C₃- alkynyl, phenyl-C₂-C₃-alkynyl, C₁-C₃-alkyl, C₁-C₃- alkoxy, formyland phenyl; or an isomer or pharmaceutically acceptable salt thereof. 7.Compound of claim 6 wherein R³is selected from hydrido, and chloro;wherein R⁴ is selected from chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, __ _ _ _pentafluoromethyl,trifluoromethylthio, trifluoromethoxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl,2,2,2-trifluoroethoxy, 2-hydroxy-1,1-dimethylethyl, phenoxy,4-methoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 2-chlorophenoxy,4-cyanophenoxy, 2,6-dimethylphenoxy, 2,4-dichlorophenoxy,3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo -4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo,ethenyl, ethynyl, chloro; and wherein R⁶is selected from hydrido,chloro, thienyl, hydroxyiminomethyl, substituted or unsubstitutedphenylethynyl, and substituted or unsubstituted phenyl; or an isomer orpharmaceutically acceptable salt thereof.
 8. Compound of claim 7 whereinR³is hydrido; wherein R⁴ is chloro or hydrido; and wherein R⁶is hydrido;or an isomer or pharmaceutically acceptable salt thereof.
 9. Compound ofclaim 8 wherein R5 is selected from 2,2,2-trifluoroethoxy,2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy,2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy,4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy,3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy,4-(trifluoromethoxy)phenoxy, 2-bromo -4-chlorophenoxy,(6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio,(4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl,(4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy,(2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, and (2-pyridinyl)oxy; or anisomer or pharmaceutically acceptable salt thereof.
 10. A compound ofFormula IIc

wherein R^(a) is selected from hydrido and lower aralkyl; wherein R′ isselected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkoxy andhalo; wherein R⁴ is selected from hydrido, halo, lower alkyl, loweralkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl,lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl,cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl,lower haloalkoxy, lower alkoxy, lower alkynyl, phenyl-lower alkynyl,lower aralkylcarbonyl, lower dialkylaminosulfonyl, loweralkylaminosulfonyl, lower aralkylaminosulfonyl, lowerheteroaralkylaminosulfonyl, 5-or 6-membered heteroaryl, lowerhydroxyalkyl, optionally substituted phenyl and 5-or 6-membered nitrogencontaining heterocyclosulfonyl; wherein R5 is selected from hydrido,lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; andwherein R′ is selected from hydrido, halo, cyano, hydroxyiminomethyl,lower hydroxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, loweralkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptablesalt thereof.
 11. Compound of claim 10 wherein R~is selected fromchloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl,pentafluoromethyl, trifluoromethylthio, trifluoromethoxy, ethynyl,phenylethynyl, substituted or unsubstituted phenylcarbonyl, andsubstituted or unsubstituted phenyl; wherein R⁵ is selected fromhydrido, methyl, tert-butyl, chloro; and wherein R⁶ is selected fromhydrido, chloro, thienyl, hydroxyiminomethyl, substituted orunsubstituted phenylethynyl, and substituted or unsubstituted phenyl; oran isomer or pharmaceutically acceptable salt thereof.
 12. Compound ofclaim 11 wherein R³is hydrido or chloro; wherein R′ is selected fromethynyl, and optionally substituted phenylethynyl; or an isomer orpharmaceutically acceptable salt thereof.
 13. A method of treating acyclooxygenase-2 mediated disorder in a subject, said method comprisingtreating the subject having or susceptible to said disorder with atherapeutically-effective amount of a compound of claims 1-12; or apharmaceutically-acceptable salt thereof.
 14. The method of claim 13wherein the cyclooxygenase-² mediated disorder is inflammation.
 15. Themethod of claim 15 wherein the Cyclooxygenase-2 mediated disorder isarthritis.
 16. The method of claim 15 wherein the cyclooxygenase-2mediated disorder is pain.
 17. The method of claim 15 wherein thecyclooxygenase-2 mediated disorder is cancer.
 18. A pharmaceuticalcomposition comprising a therapeutically-effective amount of a compound,said compound selected from a family of compounds of claims 1-12; or apharmaceutically-acceptable salt thereof.